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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.

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.

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.

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.

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.

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.)

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.)

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.

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.

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).

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.

Aim: To investigate the effects of adipose-derived stem cell (ADSC) transplantation on the angiogenesis in the brain post focal cerebral ischemia in rats., Methods: 72 male adult Sprague-Dawley rats were randomly divided into 4 groups: sham-operated group, middle cerebral artery occlusion (MCAO) group, vehicle group and MCAO+ADSC-treated group (n=18). A permenant focal cerebral ischemia model was established with the modified Longa's method. ADSC were labeled by DAPI before transplantation. One day after right MCAO, 30 muL of cell suspension containing 1x10(6) cells were injected into the lateral ventricle of MCAO+ADSC-treated group and the same dose of PBS was given to the vehicle group. On D4, D7 and D14 after MCAO, the rats were killed to detect the regeneration of microvessel and the expression of bFGF and VEGF in ischemic region by immunohistochemistry and RT-PCR., Results: A lot of microvessel proliferate in the injured cortex reached peak in 2 weeks. The microvessel density in the brain tissues of rats treated with ADSC was higher than that in MCAO group and vehicle group (P<0.01). The expression of bFGF and VEGF in the brain tissues of MCAO+ADSC-treated group was higher than that in MCAO group and vehicle group on D4, D7 and D14 post MCAO., Conclusion: The transplantation of ADSC can promote the revascularization of cerebral ischemia in rats partly by enhancing bFGF and VEGF synthesis in brain.

Vascularization, under physiological or pathophysiological conditions, typically takes place by one or more of the following processes: angiogenesis, vasculogenesis, arteriogenesis, and lymphangiogenesis. Although all of these mechanisms of vascularization have sufficient contrasting features to warrant consideration under separate cover, one common feature shared by all is their sensitivity to the VEGF signaling pathway. Conditions such as wound healing and physical exercise result in increased production of reactive oxygen species such as H(2)O(2), and both are associated with increased tissue vascularization. Understanding these two scenarios of adult tissue vascularization in tandem offers the potential to unlock the significance of redox regulation of the VEGF signaling pathway. Does H(2)O(2) support tissue vascularization? H(2)O(2) induces the expression of the most angiogenic form of VEGF, VEGF-A, by a HIF-independent and Sp1-dependent mechanism. Ligation of VEGF-A to VEGFR2 results in signal transduction leading to tissue vascularization. Such ligation generates H(2)O(2) via an NADPH oxidase-dependent mechanism. Disruption of VEGF-VEGFR2 ligation-dependent H(2)O(2) production or decomposition of such H(2)O(2) stalls VEGFR2 signaling. Numerous antioxidants exhibit antiangiogenic properties. Current evidence lends firm credence to the hypothesis that low-level endogenous H(2)O(2) supports vascular growth.

Bronchopulmonary dysplasia and emphysema are significant global health problems at the extreme stages of life. Both are characterized by arrested alveolar development or loss of alveoli, respectively. Both lack effective treatment strategies. Knowledge about the genetic control of branching morphogenesis in mammals derives from investigations of the respiratory system in Drosophila, but mechanisms that regulate alveolar development remain poorly understood. Even less is known about regulation of the growth and development of the pulmonary vasculature. Understanding how alveoli and the underlying capillary network develop, and how these mechanisms are disrupted in disease states, are critical for developing effective therapies for lung diseases characterized by impaired alveolar structure. Recent observations have challenged old notions that the development of the blood vessels in the lung passively follows that of the airways. Rather, increasing evidence suggests that lung blood vessels actively promote alveolar growth during development and contribute to the maintenance of alveolar structures throughout postnatal life. Our working hypothesis is that disruption of angiogenesis impairs alveolarization, and that preservation of vascular growth and endothelial survival promotes growth and sustains the architecture of the distal airspace. Furthermore, the explosion of interest in stem cell biology suggests potential roles for endothelial progenitor cells in the pathogenesis or treatment of lung vascular disease. In this Pulmonary Perspective, we review recent data on the importance of the lung circulation, specifically examining the relationship between dysmorphic vascular growth and impaired alveolarization, and speculate on how these new insights may lead to novel therapeutic strategies for bronchopulmonary dysplasia.

During embryogenesis, endothelial progenitor cells participate in the initial processes of primitive blood vessel formation (vasculogenesis). It has become evident that progenitors to vascular endothelial cells also exist in the adult. Endothelial progenitors normally reside in the adult bone marrow but may become mobilized into circulation by cytokine or angiogenic growth factor signals from the periphery, enter extravascular tissue, and promote de novo vessel formation by virtue of physically integrating into vessels and/or supplying growth factors (adult vasculogenesis). For that reason, autologous endothelial progenitors, mobilized in situ or transplanted, has become a major target of therapeutic revascularization approaches to ischemic disease and endothelial injury. Moreover, endothelial progenitors represent a potential target of strategies to block tumor growth.

Glycogen-Synthase Kinase 3beta (GSK3beta) has been shown to function as a nodal point of converging signaling pathways in endothelial cells to regulate vessel growth, but the signaling mechanisms downstream from GSK3beta have not been identified. Here, we show that beta-catenin is an important downstream target for GSK3beta action in angiogenesis and dissect the signal transduction pathways involved in the angiogenic phenotype. Transduction of human umbilical vein endothelial cells (HUVECs) with a kinase-mutant form of the enzyme (KM-GSK3beta) increased cytosolic beta-catenin levels, whereas constitutively active GSK3beta (S9A-GSK3beta) reduced beta-catenin levels. Lymphoid enhancer factor/T-cell factor promoter activity was upregulated by KM-GSK3beta and diminished by S9A-GSK3beta, whereas manipulation of Akt signaling had no effect on this parameter. beta-Catenin transduction induced capillary formation in a Matrigel-plug assay in vivo and promoted endothelial cell differentiation into network structures on Matrigel-coated plates in vitro. beta-Catenin activated the expression of vascular endothelial growth factor (VEGF)-A and VEGF-C in endothelial cells, and these effects were mediated at the levels of protein, mRNA, and promoter activity. Consistent with these data, beta-catenin increased the phosphorylation of the VEGF receptor 2 (VEGF-R2) and promoted its association with PI3-kinase, leading to a dose-dependent activation of the serine-threonine kinase Akt. Inhibition of PI3-kinase or Akt signaling led to a significant reduction in the pro-angiogenic activity of beta-catenin. Collectively, these data show that the growth factor-PI3-kinase-Akt axis functions downstream of GSK3beta/beta-catenin signaling in endothelial cells to promote angiogenesis.

Angiogenesis is a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases. A rich variety of pro- and antiangiogenic molecules have already been discovered. Vascular endothelial growth factor (VEGF) is an interesting inducer of angiogenesis and lymphangiogenesis, because it is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. In this article, the role of VEGF in physiological and pathological processes is reviewed. We also discuss how modulation of VEGF expression creates new therapeutic possibilities and describe recent developments in this field.

Protein and gene therapy offer a tremendous opportunity to improve the care of critically ill patients with ischemic heart and peripheral artery occlusion disease. With the availability of purified growth factors such as vascular endothelial and fibroblast growth factors (FGF), several experimental and clinical studies provided data, that the growth of capillaries (angiogenesis) and of collateral arteries (arteriogenesis) is not limited to its natural time course. When applied in experimental models and in conjunction with coronary artery bypass operations, FGF in particular, led to a significant increase in endogenous rerouting of blood flow by collateral vessels inside the tissue itself. Thus, the proliferation of preexisting bypassing arterioles could be enhanced therapeutically (biological bypass). The purpose of this review is to discuss the physiological importance of different kinds of cytokines which are able to induce angio- and arteriogenesis in ischemic limbs or the heart. It is outlined that a combination of a sufficient amount of large arterioles and a capillary network are needed to compensate perfusion deficits. Each patient, who has an ischemic area and cannot be conventionally revascularized, is a potential candidate for the biological bypass.

A review of adipose tissue angiogenesis includes the morphological and cytochemical development of adipose tissue vasculature and the concept of primitive fat organs. Spatial and temporal relationships between fetal vascular and fat cell development are discussed, including depot- and genetic-dependent arteriolar differentiation. The relationship between connective tissue deposition and elaboration of adipose tissue vasculature is discussed with respect to regulating adipocyte development in a depot-dependent manner. In vitro studies indicated that depot-dependent vascular traits may be attributable to intrinsic growth characteristics of adipose tissue endothelial cells. These studies indicate that adipogenesis may be regulated by factors that drive angiogenesis. Fundamental aspects of angiogenesis, including basement membrane breakdown, vasculogenesis, angiogenic remodeling, vessel stabilization, and vascular permeability were reviewed. Critical angiogenic factors include vascular endothelial growth factor (VEGF), VEGF receptors, angiopoietins (Ang), ephrins, matrix metalloproteinases, and the plasminogen enzymatic system. Vascular endothelial growth factor is the most critical factor because it initiates the formation of immature vessels and disruption of a single VEGF allele leads to embryonic lethality in mice. Expression of VEGF is influenced by hypoxia, insulin, growth factors, and several cytokines. Angiogenic factors secreted and/or produced by adipocytes or preadipocytes are discussed. Vascular endothelial growth factor expression and secretion by adipocytes is regulated by insulin and hypoxia, and is associated with adipose tissue accretion. Vascular endothelial growth factor accounts for most of the angiogenic activity of adipose tissue. The proposed role of leptin as an adipogenic factor is reviewed with respect to efficacy on various aspects of angiogenesis relative to other angiogenic factors. The VEGF and leptin genes are both hypoxia inducible, but potential links between VEGF and leptin gene expression have not been examined. Finally, several studies including a study of mice treated with antiangiogenic factors indicate that adipose tissue accretion can be controlled through the vasculature per se.

The intimate connection, both physical and biochemical, between blood vessels and bone cells has long been recognized. Genetic, biochemical, and pharmacological studies have identified and characterized factors involved in the conversation between endothelial cells (EC) and osteoblasts (OB) during both bone formation and repair. The long-awaited FDA approval of two growth factors, BMP-2 and OP-1, with angiogenic and osteogenic activity confirms the importance of these two processes in human skeletal healing. In this review, the role of osteogenic factors in the adaptive response and interactive function of OB and EC during the multi-step process of bone repair will be discussed.

We have shown previously that implantation of myoblasts constitutively expressing the VEGF-A gene into nonischemic mouse skeletal muscle leads to overgrowth of capillary-like blood vessels and hemangioma formation. These aberrant effects occurred directly at the implantation site. We show here that these regions result from angiogenic capillary growth and involve a change in capillary growth pattern and that smooth muscle-coated vessels similar to arterioles form directly adjacent to the implantation site. Myoblasts genetically engineered to produce VEGF were implanted into mouse leg muscles. Implantation sites were surrounded by a zone of dense capillary-sized vessels, around which was a second zone of muscle containing larger, smooth-muscle-covered vessels but few capillaries, and an outer zone of muscle exhibiting normal capillary density. The lack of capillaries in the middle region suggests that the preexisting capillaries adjacent to the implantation site underwent enlargement and/or fusion and recruited a smooth muscle coat. Capillaries at the implantation site were frequently wrapped around VEGF-producing muscle fibers and were continuous with the circulation and were not observed to include bone-marrow-derived endothelial cells. In contrast with the distant arteriogenesis resulting from VEGF delivery described in previous studies, we report here that highly localized arterioles also form adjacent to the site of delivery.