title: VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B.
abstract: Emerging evidence indicates that the tight communication between vascular endothelial cells and mural cells using platelet-derived growth factor (PDGF)-BB is essential for capillary stabilization during the angiogenic process. However, little is known about the related regulator that determines PDGF-BB expression. Using murine models of therapeutic neovascularization, we here show that a typical lymphangiogenic factor, vascular endothelial growth factor (VEGF)-C, is an essential regulator determining PDGF-BB expression for vascular stabilization via a paracrine mode of action. The blockade of VEGF type 3 receptor (VEGFR3) using neutralizing antibody AFL-4 abrogated FGF-2-mediated limb salvage and blood flow recovery in severely ischemic hindlimb. Interestingly, inhibition of VEGFR3 activity not only diminished lymphangiogenesis, but induced marked dilatation of capillary vessels, showing mural cell dissociation. In these mice, VEGF-C and PDGF-B were upregulated in the later phase after induced ischemia, on day 7, when exogenous FGF-2 expression had already declined, and blockade of VEGFR3 or PDGF-BB activities diminished PDGF-B or VEGF-C expression, respectively. These results clearly indicate that VEGF-C is a critical mediator, not only for lymphangiogenesis, but also for capillary stabilization, the essential molecular mechanism of communication between endothelial cells and mural cells during neovascularization.
authors.affiliation: Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka.
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Onimaru
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
authors.forename: Takaaki
authors.initials: T
authors.lastname: Fujii
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Tanii
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Ri-ichiro
authors.initials: R
authors.lastname: Kohno
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Katsuo
authors.initials: K
authors.lastname: Sueishi
mesh_terms: D000671:Amputation, Surgical; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000077214:Becaplermin; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D025461:Feedback, Physiological; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D015316:Genetic Therapy; D006614:Hindlimb; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D042583:Lymphangiogenesis / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012039:Regional Blood Flow; D015398:Signal Transduction; D013997:Time Factors; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000906:Antibodies; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3