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Endothelial cells acquire different phenotypes to establish functional vascular networks. Vascular endothelial growth factor (VEGF) signaling induces endothelial proliferation, migration, and survival to regulate vascular development, which leads to the construction of a vascular plexuses with a regular morphology. The spatiotemporal localization of angiogenic factors and the extracellular matrix play fundamental roles in ensuring the proper regulation of angiogenesis. This review article highlights how and what kinds of extracellular environmental molecules regulate angiogenesis. Close interactions between the vascular and neural systems involve shared molecular mechanisms to coordinate developmental and regenerative processes. This review article focuses on current knowledge about the roles of angiogenesis in peripheral nerve regeneration and the latest therapeutic strategies for the treatment of peripheral nerve injury.

A functional vascular network is essential to the correct wound healing. In sprouting angiogenesis, vascular endothelial growth factor (VEGF) regulates the formation of new capillaries from pre-existing vessels. This is a very complex process and mathematical formulation permits to study angiogenesis using less time-consuming, reproducible and cheaper methodologies. This study aimed to mimic the chemoattractant effect of VEGF in stimulating sprouting angiogenesis. We developed a numerical model in which endothelial cells migrate according to a diffusion-reaction equation for VEGF. A chick chorioallantoic membrane (CAM) bioassay was used to obtain some important parameters to implement in the model and also to validate the numerical results. We verified that endothelial cells migrate following the highest VEGF concentration. We compared the parameters-total branching number, total vessel length and branching angle-that were obtained in the in silico and the in vivo methodologies and similar results were achieved (p-value smaller than 0.5; n = 6). For the difference between the total capillary volume fractions assessed using both methodologies values smaller than 15% were obtained. In this study we simulated, for the first time, the capillary network obtained during the CAM assay with a realistic morphology and structure.

The discovery of vascular endothelial-derived growth factor (VEGF) has revolutionized our understanding of vasculogenesis and angiogenesis during development and physiological homeostasis. Over a short span of two decades, our understanding of the molecular mechanisms by which VEGF coordinates neurovascular homeostasis has become more sophisticated. The central role of VEGF in the pathogenesis of diverse cancers and blinding eye diseases has also become evident. Elucidation of the molecular regulation of VEGF and the transformative development of multiple therapeutic pathways targeting VEGF directly or indirectly is a powerful case study of how fundamental research can guide innovation and translation. It is also an elegant example of how agnostic discovery and can transform our understanding of human disease. This review will highlight critical nodal points in VEGF biology, including recent developments in immunotherapy for cancer and multitarget approaches in neovascular eye disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. Upon binding to VEGF- and neuropilin-receptor sub-types, PlGF modulates a range of neural, glial and vascular cell responses that are distinct from VEGF-A. As PlGF expression is selectively associated with pathological angiogenesis and inflammation, its blockade does not affect the healthy vasculature. PlGF actions have been extensively described in tumor biology but more recently there has been accumulating preclinical evidence that indicates that this growth factor could have an important role in retinal diseases. High levels of PlGF have been found in aqueous humor, vitreous and/or retina of patients exhibiting retinopathies, especially those with diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD). Expression of this growth factor seems to correlate closely with many of the key pathogenic features of early and late retinopathy in preclinical models. For example, studies using genetic modification and/or pharmacological treatment to block PlGF in the laser-induced choroidal neovascularization (CNV) model, oxygen-induced retinopathy model, as well as various murine diabetic models, have shown that PlGF deletion or inhibition can reduce neovascularization, retinal leakage, inflammation and gliosis, without affecting vascular development or inducing neuronal degeneration. Moreover, an inhibitory effect of PlGF blockade on retinal scarring in the mouse CNV model has also been recently demonstrated and was found to be unique for PlGF inhibition, as compared to various VEGF inhibition strategies. Together, these preclinical results suggest that anti-PlGF therapy might have advantages over anti-VEGF treatment, and that it may have clinical applications as a standalone treatment or in combination with anti-VEGF. Additional clinical studies are clearly needed to further elucidate the role of PlGF and its potential as a therapeutic target in ocular diseases., (Copyright © 2018. Published by Elsevier Ltd.)

Tumor growth and progression are critically dependent on the establishment of a vascular support system. This is often accomplished via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. VEGF ligands are overexpressed in a wide variety of solid tumors and therefore have inspired optimism that inhibition of the different axes of the VEGF pathway-alone or in combination-would represent powerful anti-angiogenic therapies for most cancer types. When considering treatments that target VEGF and its receptors, it is difficult to tease out the differential anti-angiogenic and anti-tumor effects of all combinations experimentally because tumor cells and vascular endothelial cells are engaged in a dynamic cross-talk that impacts key aspects of tumorigenesis, independent of angiogenesis. Here we develop a mathematical model that connects intracellular signaling responsible for both endothelial and tumor cell proliferation and death to population-level cancer growth and angiogenesis. We use this model to investigate the effect of bidirectional communication between endothelial cells and tumor cells on treatments targeting VEGF and its receptors both in vitro and in vivo. Our results underscore the fact that in vitro therapeutic outcomes do not always translate to the in vivo situation. For example, our model predicts that certain therapeutic combinations result in antagonism in vivo that is not observed in vitro. Mathematical modeling in this direction can shed light on the mechanisms behind experimental observations that manipulating VEGF and its receptors is successful in some cases but disappointing in others.

Objective: To evaluate the frequency of polymorphisms in the vascular endothelial growth factor (VEGF) gene, as well as to identify a potential risk haplotype among the polymorphic regions in this gene in patients with disc degeneration and in the Control Group., Methods: This study analyzed a total of 217 individuals distributed into the Disc Degeneration and Control Groups. Peripheral blood was collected from all patients to detect VEGF gene polymorphisms identified by qPCR (rs699947, rs1570360, rs2010963, rs833061 and rs3025039). All patients presenting disc degeneration had the confirmation by nuclear magnetic resonance test and were rated according to disc degeneration level., Results: All polymorphisms were in Hardy- Weinberg equilibrium (p>0.05) in the studied population. The genotypic frequency for Disc Degeneration and Control Group were rs699947 p = 0.475, rs1570360 p = 0.862, rs2010963 p = 0.823, rs833061 p=0.596 and rs3025039 p=0.230. In haplotype analysis, the compositions CAGGC (p=0.094) and CCGGC (p=0.054) stood out., Conclusion: The correlation between VEGF gene polymorphism as a risk predictor for disc degeneration was negative in the studied population. However, the VEGF gene has a large polymorphic region, and it is activated by various catabolic and metabolic factors in the disc degeneration process, which has not been fully elucidated.

Mural cells of the vertebrate brain maintain vascular integrity and function, play roles in stroke and are involved in maintenance of neural stem cells. However, the origins, diversity and roles of mural cells remain to be fully understood. Using transgenic zebrafish, we identified a population of isolated mural lymphatic endothelial cells surrounding meningeal blood vessels. These meningeal mural lymphatic endothelial cells (muLECs) express lymphatic endothelial cell markers and form by sprouting from blood vessels. In larvae, muLECs develop from a lymphatic endothelial loop in the midbrain into a dispersed, nonlumenized mural lineage. muLEC development requires normal signaling through the Vegfc-Vegfd-Ccbe1-Vegfr3 pathway. Mature muLECs produce vascular growth factors and accumulate low-density lipoproteins from the bloodstream. We find that muLECs are essential for normal meningeal vascularization. Together, these data identify an unexpected lymphatic lineage and developmental mechanism necessary for establishing normal meningeal blood vasculature.

Vascular endothelial growth factor A (VEGF) is a critical regulator of vascular development and postnatal angiogenesis and homeostasis, and it is essential for bone development and repair. Blood vessels serve both as structural templates for bone formation and they provide essential cells, growth factors and minerals needed for synthesis and mineralization, as well as turnover, of the extracellular matrix in bone. Through its regulation of angiogenesis, VEGF contributes to coupling of osteogenesis to angiogenesis, and it directly controls the differentiation and function of osteoblasts and osteoclasts. In this review, we summarize the properties of VEGF and its receptors that are relevant to bone formation and repair; the roles of VEGF during development of endochondral and membranous bones; and the contributions of VEGF to bone healing during different phases of bone repair. Finally, we discuss contributions of altered VEGF function in inherited disorders with bone defects as part of their phenotypes, and we speculate on what will be required before therapeutic strategies based on VEGF modulation can be developed for clinical use to treat patients with bone growth disorders and/or compromised bone repair. Developmental Dynamics 246:227-234, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.

Stem cells encode vascular endothelial growth factors (VEGFs), fibroblastic growth factors (FGFs), stem cell factor, stromal cell-derived factor, platelet growth factor and angiopoietin that can contribute to myocardial vascularization. VEGFs and FGFs are the most investigated growth factors. VEGFs regulate angiogenesis and vasculogenesis. FGFs stimulate vessel cell proliferation and differentiation and are regulators of endothelial cell migration, proliferation and survival. Clinical trials of VEGF or FGF for myocardial angiogenesis have produced disparate results. The efficacy of therapeutic angiogenesis can be improved by: (1) identifying the most optimal patients; (2) increased knowledge of angiogenic factor pharmacokinetics and proper dose; (3) prolonging contact of angiogenic factors with the myocardium; (4) increasing the efficiency of VEGF or FGF gene transduction; and (5) utilizing PET or MRI to measure myocardial perfusion and perfusion reserve.

Diabetic retinopathy, a sight-threatening microvascular complication of diabetes mellitus, is initiated by retinal endothelial dysfunction and succeeded by various pathological events, eventually resulting in vision-loss. These events are regulated by numerous mediators, including vascular endothelial growth factor (VEGF), which induces the progression of various events characterizing diabetic retinopathy, such as neovascularization and macular edema. VEGF is physiologically required for regulating proliferation and assembling of endothelial cells, during vasculogenesis, as well as for their maintenance and survival throughout the lifetime of blood vessels. However, various pathological conditions are induced in the body during diabetes (such as ischemia, oxidative stress and overactivation of protein kinase C), which upregulate the expression of VEGF, thereby deviating it from its physiological role and leading to various pathological demonstrations such as angiogenesis, increased permeability of endothelium, decreased inhibition of pro-apoptotic proteins and activation of various other inflammatory mediators. Such events disrupt vascular homeostasis and play key roles in the pathophysiology of diabetic retinopathy. Hence, acknowledging various VEGF-mediated pathways helps in understanding the deeper aspects related to progression of this disorder. Targeting and inhibiting VEGF-mediated disease progression might provide an effective alternative therapy and hence prove beneficial in the treatment of diabetic retinopathy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Angiogenesis is a complex biological phenomenon essential for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process but in several pathological conditions, angiogenesis results abnormal with either excessive or insufficient proliferation of blood vessels. The pro-angiogenic members of VEGF family, VEGF-A, VEGF-B and placental growth factor (PlGF), and the related receptors, VEGFR-1 and VEGFR-2, have a central and decisive role in pathological angiogenesis. Indeed, they are the targets for anti-angiogenic drugs currently approved: bevacizumab and ranibizumab, that specifically inhibit VEGF-A; aflibercept, that is able to prevent the activity of VEGF-A, VEGF-B and PlGF; several multirtarget tyrosine kinase inhibitors that are able to prevent VEGFR-1 and/or VEGFR-2 signaling. The anti-angiogenesis therapy has represented one of the most active fields of drug discovery of last decade and promises to be further expanded due the wide number of diseases for which it may by applied., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Insects combat infection through carefully measured cellular (for example, phagocytosis) and humoral (for example, secretion of antimicrobial peptides (AMPs)) innate immune responses. Little is known concerning how these different defense mechanisms are coordinated. Here, we use insect plasmatocytes and hemocyte-like Drosophila S2 cells to characterize mechanisms of immunity that operate in the haemocoel. We demonstrate that a Drosophila cytokine, growth-blocking peptides (GBP), acts through the phospholipase C (PLC)/Ca(2+) signalling cascade to mediate the secretion of Pvf, a ligand for platelet-derived growth factor- and vascular endothelial growth factor-receptor (Pvr) homologue. Activated Pvr recruits extracellular signal-regulated protein kinase to inhibit humoral immune responses, while stimulating cell 'spreading', an initiating event in cellular immunity. The double-stranded RNA (dsRNA)-targeted knockdown of either Pvf2 or Pvr inhibits GBP-mediated cell spreading and activates AMP expression. Conversely, Pvf2 overexpression enhances cell spreading but inhibits AMP expression. Thus, we describe mechanisms to initiate immune programs that are either humoral or cellular in nature, but not both; such immunophysiological polarization may minimize homeostatic imbalance during infection.

Background: It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology., Methods: Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed., Results: Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms., Conclusions: Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess the potential of anti-angiogenic treatment strategies for uterine fibroids.

Glioblastoma are one of the mostly vascularized tumors and are histologically characterized by abundant endothelial cell proliferation. Vascular endothelial growth factor (VEGF) is responsible for a degree of vascular proliferation and vessel permeability leading to symptomatic cerebral edema. Initial excitement generated from the impressive radiographic response rates has waned due to concerns of limited long-term efficacy and the promotion of a treatment-resistant phenotype. Reasons for the discrepancy between high radiographic response rates and lack of survival benefit have led to a focus on identifying potential mechanisms of resistance to antiangiogenic therapy. However, equally important is the need to focus on identification of basic mechanisms of action of this class of drugs, determining the optimal biologic dose for each agent and identify the effect of antiangiogenic therapy on oxygen and drug delivery to tumor to optimize drug combinations. Finally, alternatives to overall survival (OS) need to be pursued using the application of validated parameters to reliably assess neurologic function and quality of life.

In the mammalian ovary, the corpus luteum (CL) is a unique transient endocrine organ displaying rapid angiogenesis and time-dependent accumulation of immune cells. The CL closely resembles 'transitory tumours', and the rate of luteal growth equals that of the fastest growing tumours. Recently, attention has focused on multiple roles of immune cells in luteal function, not only in luteolysis (CL disruption by immune responses involving T lymphocytes and macrophages), but also in CL development (CL remodelling by different immune responses involving neutrophils and macrophages). Neutrophils and macrophages regulate angiogenesis, lymphangiogenesis, and steroidogenesis by releasing cytokines in the CL. In addition, functional polarisation of neutrophils (proinflammatory N1 vs anti-inflammatory N2) and macrophages (proinflammatory M1 vs anti-inflammatory M2) has been demonstrated. This new concept concurs with the phenomenon of immune function within the luteal microenvironment: active development of the CL infiltrating anti-inflammatory N2 and M2 versus luteal regression together with proinflammatory N1 and M1. Conversely, excessive angiogenic factors and leucocyte infiltration result in indefinite disordered tumour development. However, the negative feedback regulator vasohibin-1 in the CL prevents excessive tumour-like vasculogenesis, suggesting that CL development has well coordinated time-dependent mechanisms. In this review, we discuss the physiological roles of immune cells involved in innate immunity (e.g. neutrophils and macrophages) in the local regulation of CL development with a primary focus on the cow.

Purpose: The purpose of this article was to analyze the results of studies in the literature, which evaluated the use of endothelial progenitor cells (EPCs) as a cell-based tissue engineering strategy., Methods: EPCs have been successfully used in regenerative medicine to augment neovascularization in patients after myocardial infarction and limb ischemia. EPCs' important role as vasculogenic progenitors presents them as a potential source for cell-based therapies to promote bone healing., Results: EPCs have been shown to have prominent effects in promoting bone regeneration in several animal models. Evidence indicates that EPCs promote bone regeneration by stimulating both angiogenesis and osteogenesis through a differentiation process toward endothelial cell lineage and formation of osteoblasts. Moreover, EPCs increase vascularization and osteogenesis by increased secretion of growth factors and cytokines through paracrine mechanisms., Conclusion: EPCs offer the potential to emerge as a new strategy among other cell-based therapies to promote bone regeneration. Further investigations and human trials are required to address current questions with regard to biology and mechanisms of action of EPCs in bone tissue engineering.

Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The process of angiogenesis involves a complex sequence of stimuli and integrated responses, such as stimulation of endothelial cells (ECs) for their proliferation and migration, stimulation of the extracellular matrix (ECM) for the attraction of pericytes and macrophages, stimulation of smooth muscle cells for their proliferation and migration, and formation of new vascular structures. Angiogenesis is mainly an adaptive response to tissue hypoxia and depends on the accumulation of the hypoxia-inducible factor (HIF-1α) in the ischemic myocardial area, which increases the transcription of the vascular endothelial growth factor (VEGF) and its receptors VEGF-R by the ECs undergoing ischemia. Those steps involve enzymatic mechanisms and plasminogen activator proteases, metalloproteinases (MMP) of the ECM, and kinases that cause proteolytic molecular degradation of the ECM and activation and release of growth factors, such as: basic fibroblast growth factor (bFGF), VEGF, and insulin growth factor-1 (IGF-1). In the intermediate phase, stabilization of the immature neovascular sprout occurs. The final phase is characterized by vascular maturation of the physiological angiogenesis. In conclusion, coronary angiogenesis in adults is fundamentally a paracrine response of the preexisting capillary network under pathophysiological condition of ischemia and inflammation.

The ovarian hyperstimulation syndrome is a major complication of ovulation induction for in vitro fertilization, with severe morbidity and possible mortality. Whereas its pathophysiology remains ill-established, the VEGF may play a key role as well as coagulation disturbances. Risk factors for severe OHSS may be related to patients characteristics or to the management of the ovarian stimulation. Two types of OHSS are usually distinguished: the early OHSS, immediately following the ovulation triggering and a later and more severe one, occurring in case of pregnancy. As no etiologic treatment is available, the therapeutic management of OHSS should focus on its related-complications. Thrombotic complications that can occur in venous or arterial vessels represent the major risk of OHSS, possibly conducting to myocardial infarction and cerebrovascular accidents. Once the OHSS is diagnosed, prevention of thrombotic accidents remains the major issue., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Severe ischemic heart disease with refractory angina, occurs in increasing incidence. Alternative forms of treatment, in an attempt to reduce myocardial ischemia and relief of symptoms has been studied. In this context, gene therapy is an option, for the possibility of inducing angiogenesis, establish collateral circulation and reperfuse ischemic myocardium. Several clinical trials have been conducted and, except for specific cases of adverse effects, there is indication of safety, feasibility and potential effectiveness of therapy. The clinical benefit, however, is not yet well established. In this article we review the clinical trials of gene therapy for patients with ischemic heart disease. The approach includes: (1) myocardial ischemia and angiogenesis on the pathophysiological aspects involved, (2) growth factors, dealing with specific aspects and justifying the use in cardiac patients with no option for conventional therapy, (3) controlled clinical trials, where a summary of the main studies involving gene therapy for severe ischemic heart disease is presented, (4) our experience, especially on preliminary results of the first gene therapy clinical trial in Brazil and (5) future prospects.

Rationale: Orai1 and the associated calcium release-activated calcium (CRAC) channel were discovered in the immune system. Existence also in endothelial cells has been suggested, but the relevance to endothelial biology is mostly unknown., Objective: The aim of this study was to investigate the relevance of Orai1 and CRAC channels to vascular endothelial growth factor (VEGF) and endothelial tube formation., Methods and Results: In human umbilical vein endothelial cells, Orai1 disruption by short-interfering RNA or dominant-negative mutant Orai1 inhibited calcium release-activated (store-operated) calcium entry, VEGF-evoked calcium entry, cell migration, and in vitro tube formation. Expression of exogenous wild-type Orai1 rescued the tube formation. VEGF receptor-2 and Orai1 partially colocalized. Orai1 disruption also inhibited calcium entry and tube formation in endothelial progenitor cells from human blood. A known blocker of the immune cell CRAC channel (3-fluoropyridine-4-carboxylic acid (2',5'-dimethoxybiphenyl-4-yl)amide) was a strong blocker of store-operated calcium entry in endothelial cells and inhibited calcium entry evoked by VEGF in 3 types of human endothelial cell. The compound lacked effect on VEGF-evoked calcium-release, STIM1 clustering, and 2 types of transient receptor potential channels, TRPC6 and TRPV4. Without effect on cell viability, the compound inhibited human endothelial cell migration and tube formation in vitro and suppressed angiogenesis in vivo in the chick chorioallantoic membrane. The compound showed 100-fold greater potency for endothelial compared with immune cell calcium entry., Conclusions: The data suggest positive roles for Orai1 and CRAC channels in VEGF-evoked calcium entry and new opportunity for chemical modulation of angiogenesis.

With advanced aging, main components of the kidney are altered, including blood vessels, glomeruli and tubulointerstitium. Disruption in these 3 elements is interconnected and associated with several modifications, such as loss of kidney mass and systemic, metabolic and immunologic diseases. In this review we focus on renal blood vessels, the key role of hypertension and angiogenesis in the elderly kidney, the hemodynamic and molecular mechanisms underlying this aging process and the main factors involved. So far, the present data suggests a strong association between renal disease and hypertension and the impairment of regulatory mechanisms, such as angiogenesis in the aging kidney. The endothelium is a key player in vascular control and appears to be also disrupted in many compensatory functions (i.e., vasodilation). Perspectives for the management of the dysfunctional aging kidney are also addressed., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

In spite of the recent epidemiological study indicating a positive decrease in cancer trends, cancer remains to be one of the major causes of deaths and there is an anticipated increase in the number of new cancer cases to be recorded in the following years to come. It is important for researchers to improve the current therapeutic agents involved against cancer, particularly targeting to inhibit tumor cell growth, survival, and metastasis. Many researchers investigate the crucial role of a proangiogenic factor, vascular endothelial growth factor (VEGF) in the process of tumor angiogenesis, where the formation of new blood vessels carrying essential nutrients to the tumor cell becomes a critical factor for tumor growth. Since the establishment of VEGF's integral role in mediating tumor angiogenesis and tumor cell survival, current efforts are dedicated to developing therapeutic agents against VEGF and one of the emerging candidate under this category is pigment epithelium-derived factor (PEDF)., (Copyright © 2010 Wiley-Liss, Inc.)

Objective: The purpose of this study was to describe the probable mechanism of the volume increase of laparoscopically harvested omentum flaps used to treat breast deformities., Methods: A histological analysis of omentum samples was performed to study the volume increase of laparoscopically harvested omentum flaps. Samples were harvested immediately after the transposition of the omentum from the abdominal cavity to the breast region and during the second surgical procedure for breast symmetrization of eight patients submitted to the transposition of the omentum flap. Changes in the morphometric measurements of the adipocytes (perimeter, diameter, and area), microvascular density (as measured by the CD31 endothelial marker), and immunohistochemical expression of VEGF were documented., Results: The increases in adipocyte size and microvascular density were statistically significant (P < 0.012). The expression levels of VEGF were lower in the second set of samples when compared to the first set, but the differences were not statistically significant (P < 0.093)., Conclusion: These results demonstrate an increase in cellular volume as measured by adipocyte perimeter, diameter, and area. Moreover, the increase in the number of vessels in the second set of samples suggests that neoangiogenesis was stimulated by the initial increase in VEGF expression levels observed in the first set of samples. The increase in VEGF expression in the flap may have been caused by adipocyte hypertrophy resulting from neoangiogenesis.

Neuropilins comprise two homologous widely-expressed single-pass plasma membrane receptors (Nrp1 and Nrp2), originally identified for binding secreted Semaphorins and Vascular Endothelial Growth Factors (in association with Plexins and VEGF-Receptors). Semaphorins have been implicated with opposite functions in cancer: either as putative tumor suppressors and anti-angiogenic factors, or mediating tumour angiogenesis, invasion and metastasis. Moreover, due to their implication in VEGF signaling, neuropilins regulate vascular development and tumor angiogenesis. Recent evidence further suggests a role of neuropilins in cancer progression due to their interaction with receptor tyrosine kinases, adhesion molecules, and integrins. Furthermore, neuropilins have been implicated in response to additional growth factors, such as Hepatocyte Growth Factor, Fibroblast Growth Factor, Transforming Growth Factor beta, Galectin, etc. Altogether, these data seem to qualify neuropilins as signaling platforms on the cell surface, potentially capable of regulating cancer cells, as well as cells of the tumor microenvironment. Intriguingly, clinical-pathological data often indicate a correlation between increased expression of neuropilins and advanced stage tumors with poor prognosis. In this article, we will review the current experimental evidence about the functional role of neuropilins in cancer and the underlying molecular mechanisms.

Research on blood vessel formation has provided a great deal of information regarding both normal and pathological forms of angiogenesis during development and in different disease states. Central to these studies is the role of the vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). VEGF stimulation promotes the division, survival, and migration of endothelial cells, and is necessary for the formation of blood and lymphatic vessels. The conserved functions of the VEGF ligands and receptors from fish to mammals have allowed a near-seamless translation of a cellular and molecular mechanism of vascular assembly between vertebrate models. An added advantage to the conserved gene function is the ability to apply chemical approaches to modulate zebrafish angiogenesis. In this chapter we will discuss current and potential future uses of chemical strategies in the zebrafish model to further our understanding of angiogenesis, lymphangiogenesis, and regenerative biology., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Lymphangiogenesis remains a fascinating biological process that plays a crucial role in both normal tissue development and several lymphatic diseases. The last few years have witnessed a rapid progression in understanding the development and regulation of the lymphatic system which provided insight on several pathological processes including cancer lymphatic metastasis. Lymphatic vasculature serves as a major route for tumour metastasis. The dissemination of malignant cells to the regional lymph nodes is an early step in the progression of many solid tumours and is an important determinant of staging and prognosis. Lymphangiogenesis is thought to play a pivotal role for cancer cells to metastasis to the regional lymph nodes. Several human solid tumours are now considered to be lymphangiogenic i.e. they have the ability to induce their own lymphatic vessels to establish metastasis. Hence, targeting lymphangiogenesis by developing anti-lymphangiogenic agents might constitute a novel way to prevent lymphatic progression in some tumours. Here, we have reviewed the development of the lymphatic system, the regulation of lymphangiogenesis and explored its relation to several human cancers.

Diabetes Mellitus (DM) is an important risk factor of erectile dysfunction (ED). We sought to investigate the nature and mechanism of the vasoreactivity in Akita (Ins2 [WT/C96Y]) mice, a model of genetic nonobese Type 1 diabetes that recapitulates human Type 1 diabetes. Eight wild-type (WT) mice (group 1) and 8 Akita mice (group 2) were used for this study. Corporal tissues were harvested and studied for endothelium-dependent and endothelium-independent vasoreactivities by isometric tension study; levels of vascular endothelial growth factor (VEGF) and cyclic guanosine monophosphate (cGMP) were studied with the use of enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent and endothelium-independent vasoreactivities, cGMP, and VEGF were significantly decreased in the corporal tissues of Akita mice. Corporal tissues from Akita mice demonstrate many of the major functional and biochemical changes found in humans with ED. This model could serve as a valuable tool for advancing our understanding of the role DM plays in the pathogenesis of ED.

Vascular endothelial growth factor (VEGF) stimulates nitric oxide (NO) production, which mediates many of its angiogenic actions. However, the angiogenic pathways that operate downstream of NO following VEGF treatment are not well characterized. Herein, we used DT-2 and DT-3, two highly selective cGMP-dependent protein kinase I peptide inhibitors to determine the contribution of PKG-I in VEGF-stimulated angiogenesis. Incubation of chicken chorioallantoic membranes (CAM) with PKG-I peptide inhibitors decreased vascular length in a dose-dependent manner, with DT-3 being more effective than DT-2. Moreover, inhibition of PKG-I with DT-3 abolished the angiogenic response elicited by VEGF in the rabbit eye cornea. PKG-I inhibition also blocked VEGF-stimulated vascular leakage. In vitro, treatment of cells with VEGF stimulated phosphorylation of the PKG substrate VASP through VEGFR2 activation; the VEGF-stimulated VASP phosphorylation was reduced by DT-2. Pre-treatment of cells with DT-2 or DT-3 inhibited VEGF-stimulated mitogen-activated protein kinase cascades (ERK1/2 and p38), growth, migration and sprouting of endothelial cells. The above observations taken together identify PKG-I as a downstream effector of VEGFR2 in EC and provide a rational basis for the use of PKG-I inhibitors in disease states characterized by excessive neovascularization., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The incidence of cardiovascular disease is increasing worldwide. Despite many new developments in 60(th) medical and surgical specialities, a substantial number of cardiac patients are not suitable candidates for one of the current treatment options. This "no-option" subgroup of patients is a driving influence in the rapidly developing field of angiogenesis. In this review, we discuss the different modalities of treatment being tried for these patients and the patents which have been filed to improve cardiac angiogenesis.

Background: Angiopoetin- (Ang-) 1 inhibits and Ang-2 promotes VEGF-mediated angiogenesis via binding to endothelial cell-bound Tie-2 receptor (Tie-2). After minimally invasive colorectal resection (MICR), Ang-1 levels decrease and Ang-2 levels increase, which may stimulate angiogenesis in wounds and residual tumor foci. Soluble Tie-2 (sTie-2) modulates the effects of free Ang-1 and Ang-2 by binding to them. This study assessed perioperative MICR plasma sTie-2 levels., Methods: Blood samples were taken preoperatively (PreOp) and on postoperative days (POD) 1 and 3 from 50 cancer and 53 benign disease MICR patients. In a subgroup, a fourth sample was taken between POD7 and POD13 and bundled as a single time point. sTie-2 levels (ng/ml) were determined via ELISA. The mean and SD were determined at each time point. The t test used for analysis., Results: PreOp plasma sTie-2 levels were significantly higher in the benign group (27.6 ± 10.2) than in the cancer group (22.9 ± 7.9). A significant drop from PreOp occurred in sTie-2 levels in the cancer group on POD1 (20.0 ± 7.4) and POD3 (21.0 ± 6.6) and in the benign group on POD1 (24.8 ± 9.1). The benign group's POD3 and the cancer group's POD7-13 sTie-2 levels were statistically similar to the PreOp levels while the benign group's POD7-13 level was significantly higher., Conclusion: PreOp sTie-2 levels were significantly lower in cancer patients. MICR is associated with a significant short-lived decrease in plasma sTie-2 levels in cancer patients on POD1 and 3, which may briefly inhibit VEGF-mediated angiogenesis. The benign group's early results were similar.

N-arachidonoyl serine (ARA-S) is one of a number of acyl amino acids recently identified in mammalian tissues. It has been referred to as an endocannabinoid-like lipid largely based on its structural similarities with the endocannabinoid, N-arachidonoyl ethanolamide (anandamide). However, little is known about its potential physiological functions and receptor targets. In this issue of the British Journal of Pharmacology, Zhang and colleagues show that ARA-S is a potent inducer of endothelial cell proliferation and migration, and angiogenesis in vitro. Furthermore, this pro-angiogenic action is mediated, at least partly, by activation of the poorly characterized, G-protein-coupled GPR55 receptor. ARA-S, via GPR55, increases phosphorylation of extracellular signal-regulated kinases and Akt, and vascular endothelial growth factor signalling. These exciting findings highlight the endothelium as an endogenous target for ARA-S and GPR55.

Objectives: Cyclooxygenase 2 (COX-2) and vascular endothelial growth factor (VEGF), often coexpressed in cancer, are associated with poor prognosis. However, results from pancreatic cancer trials of their inhibitors were disappointing. This study delineated the role of COX-2 and nonsteroidal anti-inflammatory drugs in angiogenesis and VEGF regulation., Methods: AsPC-1 and BxPC-3 pancreatic cancer cells were cocultured with human umbilical vein endothelial cells (HUVECs). NS398 or VEGF-neutralizing antibody was added, and HUVEC viability assayed. Prostaglandin E2 and VEGF were quantified. Tumor cells were treated with NS398 or celecoxib, and VEGF quantified., Results: In cocultures, HUVEC viability in AsPC-1 was 60% that of BxPC-3 controls (P < 0.05). Prostaglandin E2 and VEGF from BxPC-3 were double that of AsPC-1 (P < 0.05). NS398 reduced prostaglandin E2 to undetectable levels (P < 0.05) but had no effect on HUVEC viability. Vascular endothelial growth factor-neutralizing antibody reduced HUVEC viability in BxPC-3 wells to that of AsPC-1 (P < 0.05). NS398 had no effect on VEGF. Celecoxib increased VEGF in a concentration-dependent manner in each cell line up to 4-fold (P < 0.05)., Conclusions: Cyclooxygenase 2 does not regulate VEGF in pancreatic cancer, and celecoxib upregulates VEGF in pancreatic cancer. It is VEGF, and not COX-2, inhibitors that reduce tumor-stimulated endothelial cell viability. Future pancreatic cancer trials should consider lower-dose nonsteroidal anti-inflammatory drugs in combination with VEGF inhibitors.

1. Hydrogen sulphide (H(2)S) has recently been recognized as a gasotransmitter that regulates angiogenesis in vitro and in vivo under physiological and ischaemic conditions. 2. In the present review, the mechanisms underlying angiogenesis are summarized briefly and the most recent progress in H(2)S-induced angiogenesis in vivo and in vitro is described. The anti-angiogenic effects of garlic extracts, which may serve as substrates for H(2)S-generating enzymes in vivo, are also discussed. 3. Hydrogen sulphide increases cell growth, migration and the formation of tube-like structures in cultured endothelial cells. These effects are dependent on activation of the phosphatidylinositol 3-kinase-Akt-survivin signalling pathway. Neovascularization in vivo has also been demonstrated to be promoted in the mouse Matrigel plug assay, as well as in chicken chorioallantoic membranes. In a rat unilateral hindlimb ischaemic model, treatment with sodium hydrosulphide (NaHS), an H(2)S donor, promotes significant angiogenesis and improves regional blood flow. These effects may be mediated by interactions between upregulated vascular endothelial growth factor (VEGF) in skeletal muscle cells and VEGF receptor 2 and the downstream signalling element Akt in vascular endothelial cells. However, H(2)S does not exhibit a pro-angiogenic effect at a high concentrations/doses. 4. Based on the studies reviewed in the present article, we assume that, at physiologically relevant doses/concentrations, H(2)S/HS(-) promote angiogenesis at least partly via the VEGF signalling pathway. At high doses, H(2)S/HS(-) may act on additional cellular targets to evoke mechanisms that counteract the pro-angiogenic pathways. More studies need to be performed analysing the general interactions between H(2)S/HS(-) and other molecules, including other gasotransmitters, such as nitric oxide and carbon monoxide (CO).

The aim of this study was to investigate the strategic role of vascular endothelial growth factor (VEGF) in the pathophysiology of polycystic ovary syndrome (PCOS) and to critically review the published trials that have evaluated VEGF in women with PCOS. An electronic database search of Medline, Embase, Cinahl and Cochrane library was conducted. Studies were included if they evaluated VEGF either in the circulation or in granulosa lutein cell culture media in in-vitro laboratory studies of women with a polycystic ovary (PCO) or PCOS. Studies analysing immunohistochemical expression of VEGF in PCO were also included. This review concluded that VEGF may have a strategic role in the pathophysiology of PCOS and is the key mediator in the pathogenesis of ovarian hyperstimulation syndrome (OHSS) in women undergoing assisted reproductive procedures. Its role is perhaps not singular and several other factors such as the bioavailability of its soluble receptor sFlt-1 and a multidisciplinary orchestration of other cytokines and growth factors may be involved in the pathophysiology of PCOS and OHSS., (Copyright (c) 2010. Published by Elsevier Ltd.)

Adenoviral transduction of the VEGF gene in an oversized skin flap increases flap survival and perfusion. In this study, we investigated the potential of magnetofection of magnetic lipospheres containing VEGF(165)-cDNA on survival and perfusion of ischemic skin flaps and evaluated the method with respect to the significance of applied magnetic field and ultrasound. We prepared perfluoropropane-filled magnetic lipospheres ('magnetobubbles') from Tween60-coated magnetic nanoparticles, Metafectene, soybean-oil and cDNA and studied the effect in an oversized random-pattern-flap model in the rats (n= 46). VEGF-cDNA-magnetobubbles were administered under a magnetic field with simultaneously applied ultrasound, under magnetic field alone and with applied ultrasound alone. Therapy was conducted 7 days pre-operative. Flap survival and necrosis were measured 7 days post-operatively. Flap perfusion, VEGF-protein concentration in target and surrounding tissue, formation and appearance of new vessels were analysed additionally. Magnetofection with VEGF-cDNA-magnetobubbles presented an increased flap survival of 50% and increased flap perfusion (P < 0.05). Without ultrasound and without magnetic field, the effect is weakened. VEGF concentration in target tissue was elevated (P < 0.05), while underlying muscle was not affected. Our results demonstrate the successful VEGF gene therapy by means of magnetobubble magnetofection. Here, the method of magnetofection of magnetic lipospheres is equally efficient as adenoviral transduction, but has a presumable superior safety profile.

Angiogenesis has a key role for embryonic development and is crucial in several major diseases. Molecular basis of angiogenesis has been widely investigated (J Biochem Mol Biol. 2006;39:469-478, Oncogene. 2000;19:5598-5605). In this review, vascular endothelial growth factor (VEGF) and related receptors and their key roles in embryonic bladder development are discussed. The normal VEGF expression and related angiogenesis pattern of embryonic bladder are highlighted. The VEGF family especially VEGF-A is the major player in angiogenesis as well as many other angiogenic factors and activates 2 tyrosine kinase receptors, VEGFR-1 and VEGFR-2 (J Biochem Mol Biol. 2006;39:469-478). Besides its worthy role in angiogenesis, VEGF-A also seems to participate in normal bladder development (J Urol. 2007;177:1552-1557, Br J Urol Int. 2006;98:217-225). In previous studies, we have shown that exogenous VEGF or hypoxia-induced endogenous upregulation of this protein accelerates the growth of the bladder by detrusor and urothelium hypertrophy and hyperplasia (J Urol. 2007;177:1552-1557, Br J Urol Int. 2006;98:217-225, Dev Biol. 1997;183:139-149, Neurourol Urodyn. 2004;23:342-348). This abrupt role of VEGF on detrusor muscle through a hypoxic pathway may potentially be a part of the solution for many urologic conditions such as remodeling of detrusor muscle in antenatal bladder outlet obstruction., (Copyright 2010 Elsevier Inc. All rights reserved.)

Hypoxia-inducible factor 1 (HIF1) has been demonstrated to have critical roles in angiogenesis via transcriptional regulation of angiogenic factors, such as vascular endothelial growth factor (VEGF). In the ovary, angiogenesis is known to occur after ovulation in the developing corpus luteum (CL) in mammals. To determine whether HIF1 participates in angiogenesis in bovine CL, the present study investigated the mRNA and protein expressions of the HIF1 alpha subunit (HIF1A) and VEGF in bovine CL during the estrous cycle. The effects of hypoxia on the expressions of HIF1A protein, VEGF mRNA and VEGF protein in bovine luteal cells were also examined by using a cell culture system. HIF1A mRNA expression was less at the regressed stage than at the other stages, whereas protein expression of HIF1A was highest at the early luteal stage and decreased thereafter. VEGF mRNA expression was highest at the developing luteal stage and decreased thereafter. VEGF protein expression was highest at the early luteal stage and decreased significantly at the regressed luteal stage. Hypoxia increased the amounts of HIF1A protein, VEGF mRNA and VEGF protein in cultured bovine luteal cells. Furthermore, we found that hypoxia inhibited progesterone production in the mid luteal cells, but not in the early luteal cells. The overall findings indicate that HIF1 is one of the factors promoting VEGF-induced angiogenesis during luteal development, and suggest that the hypoxic conditions formed after follicle rupture contribute to establishing luteal vascularization in cattle.

Induction of neo-angiogenesis is a fundamental step in many pathological conditions. The therapeutic value of inhibiting angiogenesis is an interesting area of research in oncology, with vascular endothelial growth factor (VEGF) being the most suitable anti-angiogenic target. In the last decade a number of anti-VEGF drugs have demonstrated, especially in combination with standard chemotherapy, clinical efficacy in the treatment of different solid tumor types. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a permeability, proliferation, and migration factor, is also a maintenance and protection factor for endothelial cells, being capable of regulating multiple biological functions, i.e. the production of vasoactive mediators and the expression of components of the thrombolytic and coagulation pathways. Consequently, the disturbance of vascular homeostasis by blocking VEGF may lead to endothelial dysfunction and adverse vascular effects, such as venous and arterial thromboembolic events. In preclinical models angiogenesis and the increased expression of VEGF has been associated to altered expression of proinflammatory genes. These genes may be regulated in a biphasic manner, and it is possible that anti-VEGF therapy may disrupt a negative feedback loop that leads to potential in situ thrombus formation. Accordingly, combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was recently associated with an increased risk of thromboembolism. The present review considers the biological mechanisms and clinical impact of thromboembolic complications during anti-angiogenic treatments in cancer patients.

Vascular endothelial growth factor (VEGF) is a main regulator of blood vessel growth and plays an important role in promoting endothelial survival and maintaining the microvasculature. The kidney is a highly vascularized organ and has two important microvasculatures; glomerular and peritubular capillaries. Loss of these capillaries is strongly associated with the progression of chronic kidney disease (CKD) to end-stage renal disease. In several kidney disease animal models, VEGF expression in the kidney is decreased and administration of VEGF is protective. Recent clinical observations revealed that blocking VEGF by endogenous inhibitor (soluble Flt-1) in preeclampsia and monoclonal antibody against VEGF in cancer patients cause proteinuria and renal dysfunction. However, plasma VEGF levels in diabetic nephropathy patients are increased and blocking VEGF improved diabetic nephropathy in animal models. Increased plasma VEGF levels have been reported in CKD patients. Deleterious effects of VEGF have been demonstrated in atherosclerosis and sepsis, which are frequent complications in CKD patients. Although administrating VEGF or novel drugs that activate VEGF pathway may improve the progression of CKD, careful monitoring will be required when CKD patients have complications of diabetes, atherosclerosis or sepsis.

The purpose of this study was to examine the influence of adenovirus-carried VEGF165 transgene at 5 x 10(10) pfu (Ad-VEGF) on vascular formation, cardiac geometry and ventricular function in infarcted hearts of the rat and to explore the mechanism of Ad-VEGF-mediated actions on ventricular function by quantitative proteomic analysis. Seven days after coronary occlusion, intramyocardial injection with normal saline (vehicle control), adenovirus-carried beta-galactosidase gene (Ad-LacZ, vector control) or Ad-VEGF to infarcted hearts was conducted. Seven days after intramyocardial injection, ventricular function, cardiac morphology and vascular density were assessed after echocardiographic analysis and immunohistological staining. One dimensional gel electrophoresis coupled with stable isotope dimethyl labeling and LC/MS/MS was used to quantify the abundance ratio of each protein pair in Ad-VEGF- and Ad-LacZ-treated hearts. Our data indicated that both Ad-VEGF and Ad-LacZ increased arteriolar densities. However, the former increased arterial densities but the latter did not. Compared with the vehicle control, Ad-LacZ reversed occlusion-induced wall thinning and functional impairment but Ad-VEGF did not. Quantitative proteomic analysis showed increased ratios of plasma proteins (such as albumin) and oxygen carriers (such as myoglobin) by Ad-VEGF and decreased ratios of proteins involved in glycolysis, calcium homeostasis and lipolysis by Ad-VEGF. Taken together, our functional, morphological and proteomic data suggest that intramuscular delivery of Ad-LacZ at higher doses may improve ventricular function and wall thinning with arteriolar formation. Excessive amounts of VEGF by Ad-VEGF may offset Ad-LacZ-induced improvement in ventricular functions by interfering with calcium homeostasis and lipolysis in infarcted hearts.

Fatty acid binding protein 4 (FABP4) plays an important role in maintaining glucose and lipid homeostasis. FABP4 has been primarily regarded as an adipocyte- and macrophage-specific protein, but recent studies suggest that it may be more widely expressed. We found strong FABP4 expression in the endothelial cells (ECs) of capillaries and small veins in several mouse and human tissues, including the heart and kidney. FABP4 was also detected in the ECs of mature human placental vessels and infantile hemangiomas, the most common tumor of infancy and ECs. In most of these cases, FABP4 was detected in both the nucleus and cytoplasm. FABP4 mRNA and protein levels were significantly induced in cultured ECs by VEGF-A and bFGF treatment. The effect of VEGF-A on FABP4 expression was inhibited by chemical inhibition or short-hairpin (sh) RNA-mediated knockdown of VEGF-receptor-2 (R2), whereas the VEGFR1 agonists, placental growth factors 1 and 2, had no effect on FABP4 expression. Knockdown of FABP4 in ECs significantly reduced proliferation both under baseline conditions and in response to VEGF and bFGF. Thus, FABP4 emerged as a novel target of the VEGF/VEGFR2 pathway and a positive regulator of cell proliferation in ECs.

The vascular endothelial growth factor (VEGF) family of proteins regulates blood flow, growth, and function in both normal physiology and disease processes. VEGF-A is alternatively spliced to form multiple isoforms, in two subfamilies, that have specific, novel functions. Alternative splicing of exons 5-7 of the VEGF gene generates forms with differing bioavailability and activities, whereas alternative splice-site selection in exon 8 generates proangiogenic, termed VEGF(xxx), or antiangiogenic proteins, termed VEGF(xxx)b. Despite its name, emerging roles for VEGF isoforms on cell types other than endothelium have now been identified. Although VEGF-A has conventionally been considered to be a family of proangiogenic, propermeability vasodilators, the identification of effects on nonendothelial cells, and the discovery of the antiangiogenic subfamily of splice isoforms, has added further complexity to their regulation of microvascular function. The distally spliced antiangiogenic isoforms are expressed in normal human tissue, but downregulated in angiogenic diseases, such as cancer and proliferative retinopathy, and in developmental pathologies, such as Denys Drash syndrome and preeclampsia. Here, we examine the molecular diversity of VEGF-A as a regulator of its biological activity and compare the role of the pro- and antiangiogenic VEGF-A splice isoforms in both normal and pathophysiological processes.

Neoangiogenesis, the development of new blood vessels from a pre-existing vasculature involves the migration behavior, proliferation and differentiation of endothelial cells. This process is an important aspect to both the growth and metastasis of solid tumors. In growing tumors, the development of a sufficient vascular supply is a highly complex event, which is controlled by many factors. An interaction between tumor cells, endothelial cells, macrophages, fibroblasts, and the extracellular matrix, all of which are capable of releasing factors influencing the angiogenic mechanisms is necessary for the building of new sufficient vascular structures. The increased understanding of the balance of angiogenesis and mechanisms of vascular control allowed the development of new therapeutic substances that influence that process in different ways. For example, work done over the last decade has elucidated the central role of vascular endothelial growth factor (VEGF) in the regulation of normal and pathological angiogenesis. Therefore, the blockade of VEGF signaling is currently a major part of strategies for the therapy of malignant tumors. Several studies tested neutralizing antibodies against mature VEGF protein or its isoforms, blockade of VEGF receptors by VEGF receptor antibodies, soluble VEGF receptor mutants or fusion-proteins and finally, intracellular interference with VEGF mRNA or signaling in the target cell. In this review, we present strategies and substances for the blockade of neoangiogenesis that are already in clinical use or in pre-clinical trials. Also the combination of these approaches with conventional chemotherapy or radiotherapy will be discussed.