The transition of the late anagen to the catagen phase is concomitant with the disappearance of perifollicular capillaries, and therefore cyclical hair growth might depend on the ability of the dermal papilla to synthesize and release soluble growth and differentiation factors toward pre-existing capillaries. We characterized an angiogenic growth factor in the conditioned medium of dermal papilla cells indistinguishable from vascular endothelial growth factor as judged by biochemical and immunologic criteria. In addition, these cells bind vascular endothelial, growth factor on two binding sites and proliferate or migrate in the presence of this growth factor. Moreover, neutralizing antibodies inhibit these biologic effects, confirming that vascular endothelial growth factor might contribute to hair growth either by acting directly on papilla cells or by stimulating the local vascularization.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor which is synthesized and secreted by many differentiated cells in response to various stimuli including hypoxia and growth factor exposure. Alternative splicing of vascular endothelial growth factor mRNA results in three distinct molecular forms: V189 and V165 or V121 which lack the exons 6 or 6 and 7, respectively. To clarify the functions of the 24-amino acid insertion, the biological activity of V165 was compared with that exerted by purified recombinant V189 and a synthetic peptide designed on the sequence encoded by exon 6 (Ex6P). V189 and Ex6P, but not V165, induced cell proliferation on corneal endothelial cells cultured in vitro. These effects were due to the release of fibroblast growth factor 2 (FGF2) stored in the extracellular matrix but not to direct interactions with FGF receptors since V189 was inefficient on heparan sulfatedeficient cells expressing constitutively FGF-R1. Moreover corneas incubated ex vivo with Ex6P solubilized 10-fold more FGF2 than a isocationic peptide containing a scrambled sequence. Ex6P elicited an angiogenic response in a corneal pocket assay which was totally inhibited by addition of anti-FGF2 IgG. Moreover the angiogenic response to V189, but not to V165, was inhibited by FGF2 immunoneutralization. These findings demonstrate that the presence of the exon 6-encoded sequence confers VEGF with the ability to exert its biological effects through FGF2 signaling pathways.

The proposed system of analysis and reporting could prove clinically relevant in the decision whether to repeat targeted biopsies.

Ž. Objective: The concept of therapeutic angiogenesis with vascular endothelial growth factor VEGF has been validated in peripheral arterial disease. Its use in myocardial ischemia may be delayed as the result of the description in a porcine model of peripheral vasodilation after intraluminal injections of VEGF resulting in a 50% fatality rate by hypotension. We carried out this study to test Ž . Ž . Ž . whether VEGF-induced hypotension 1 is species specific, 2 is mediated by the receptor mediating angiogenesis, 3 is prevented by inhibition of nitric oxide synthase. Methods: In the rabbit corneal pocket assay we tested whether a previously published anti-idiotypic Ž . antibody AIA agonist of the VEGF receptor Flk-1rKDR could elicit angiogenesis. Various doses of recombinant VEGF or AIA were Ž . injected into anesthetized normotensive Wistar-Kyoto rats and the mean arterial blood pressure MABP was recorded. To test the implication of nitric oxide in VEGF-induced hypotension we treated the animals with a competitive inhibitor of nitric oxide synthase prior to the injection of VEGF. Results: Both VEGF and AIA induce angiogenesis but only intravenous injections of VEGF induced a rapid, transient and dose-dependent decrease in MABP. The ED50 was 0.5 mg. The interval between two VEGF injections required to lead to a decrease of MABP was 40 minutes. Nitric oxide synthesis inhibitor prevented, in a reversible fashion, the effect of VEGF. Conclusion: VEGF-induced hypotension is not species specific. It is prevented by nitric oxide inhibition. VEGF-induced angiogenesis and hypotension are not mediated in vivo by the same VEGF receptor q 1997 Elsevier Science B.V.