Differential role of platelet granular mediators in angiogenesis.
OBJECTIVE
Platelets contain numerous substances regulating angiogenic response. However, the regulatory role of platelets in blood vessel development remains to be elucidated. We investigated the comprehensive effect of platelets as a cellular system on angiogenesis.


METHODS
The following approaches were applied: (a) in vitro-aortic ring assay and chemotaxis assay; (b) in vivo-injection of platelet-containing matrigel plug subcutaneously into a mouse followed by immunohistochemical analysis of angiogenic response.


RESULTS
Platelets stimulated formation of blood vessels in vitro in the rat aortic ring model via VEGF and bFGF, while blocking of platelet factor-4 promoted this effect. Addition of platelets to the matrigel followed by its subcutaneous injection into a mouse resulted in an intensive migration of fibroblasts into the matrigel as well as formation of blood capillaries de novo. This platelet effect was mediated through bFGF, VEGF, and heparanase. Furthermore, platelet releasate was found to induce endothelial cell chemotaxis. This effect was mediated by a concerted action of intraplatelet bFGF, PDGF, VEGF, and heparanase.


CONCLUSIONS
Platelets affect different stages of the angiogenic response with a trend to a pro-angiogenic net effect despite the presence of angiogenesis inhibitors such as platelet factor 4. While a concomitant effect of bFGF and VEGF seemed to be essential for the entire process of vessel formation (aortic ring and matrigel models), PDGF and heparanase were effective only at the migration stage.
Brill
Alexander
A
Blood Coagulation Unit, Hematology Department, Hadassah Medical Center, Jerusalem, Israel. brilla@hadassah.org.il
Elinav
Hila
H
Varon
David
D
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001011:Aorta; D001792:Blood Platelets / Q000502:physiology*; D002196:Capillaries / Q000473:pathology; D002465:Cell Movement; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D016222:Fibroblast Growth Factor 2 / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D019763:Heparin Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007797:Laminin; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic; D010978:Platelet Factor 4 / Q000276:immunology / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000276:immunology / Q000378:metabolism; D011509:Proteoglycans; D051381:Rats; D011919:Rats, Inbred Strains; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D019138:Antibodies, Blocking; D004338:Drug Combinations; D007797:Laminin; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D010978:Platelet Factor 4; D003094:Collagen; D019763:Heparin Lyase