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Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis., Author(s): Annelii Ny [1, 5]; Marta Koch [1, 5]; Martin Schneider [1, 5]; Elke Neven [1, 5]; Ricky T Tong [2, 5]; Sunit Maity [1]; Christian Fischer [1]; Stephane Plaisance [...]

Therapeutic angiogenesis is likely to require the administration of factors that complement each other. Activation of the receptor tyrosine kinase (RTK) Flk1 by vascular endothelial growth factor (VEGF) is crucial, but molecular interactions of other factors with VEGF and Flk1 have been studied to a limited extent. Here we report that placental growth factor (PGF, also known as PlGF) regulates inter- and intramolecular cross talk between the VEGF RTKs Flt1 and Flk1. Activation of Flt1 by PGF resulted in intermolecular transphosphorylation of Flk1, thereby amplifying VEGF-driven angiogenesis through Flk1. Even though VEGF and PGF both bind Flt1, PGF uniquely stimulated the phosphorylation of specific Flt1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor cross talk through formation of Flk1/Flt1 heterodimers. The inter- and intramolecular VEGF receptor cross talk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone., Author(s): Monica Autiero [1, 12]; Johannes Waltenberger [2, 12]; Didier Communi [1, 12]; Andrea Kranz [2]; Lieve Moons [1]; Diether Lambrechts [1]; Jens Kroll [2]; Stephane Plaisance [1]; Maria De [...]

Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf[sup.164] isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf[sup.164]-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome., Author(s): Ingeborg Stalmans [1, 12]; Diether Lambrechts [1, 12]; Frederik De smet [1]; Sandra Jansen [1]; Jian Wang [5]; Sunit Maity [1, 6]; Paige Kneer [5]; Maren von der Ohe [...]

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na[sup.+] channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A[sup.[DELTA]/+]) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a[sup.[DELTA]/+] mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a[sup.[DELTA]/+] mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome., Author(s): Dieter Nuyens [1]; Milan Stengl [2]; Saran Dugarmaa [4]; Tom Rossenbacker [1]; Veerle Compernolle [1]; Yoram Rudy [5]; Jos F. Smits [3]; Willem Flameng [6]; Colleen E. Clancy [5]; [...]

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf[sup.-/-]). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf[sup.-/-] mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf[sup.-/-] mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders., Author(s): Peter Carmeliet (corresponding author) [1]; Lieve Moons [1]; Aernout Luttun [1]; Valeria Vincenti [2]; Veerle Compernolle [1]; Maria De Mol [1]; Yan Wu [3]; Francoise Bono [4]; Laetitia Devy [...]

In the absence of vascular endothelial growth factor genes, VEGF(sub.164) and VEGF(sub.188), in mice, impaired myocardial angiogenesis is seen as are reduced myocardial perfusion and fatal ischemic cardiomyopathy. The pursuit of gene therapy strategies of ischemic heart disease led researchers to generate the mice using targeted embryonic stem cells.

Focuses on impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF. Generation of VEGF in mice; Impaired cardiac performance; Impaired myocardial angiogenesis.

Focuses on impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF. Generation of VEGF in mice; Impaired cardiac performance; Impaired myocardial angiogenesis.