Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2

Abstract

Abstract-In the present study we hypothesized that endothelial progenitor cells (EPCs) enhance production of vasoprotective substances in cerebral arteries. Isolated mononuclear cells from rabbit peripheral blood were cultured in endothelial growth medium (EGM-2) for 7 days to yield EPCs. Rabbit basilar arteries were exposed to autologous EPCs (Ϸ5ϫ10 5 cells) in vitro or in vivo. Twenty-four hours after intracisternal delivery of autologous EPCs, basilar arteries were isolated and expression of vasoregulatory proteins, production of prostacyclin (PGI 2 ), and cAMP were determined. Arteries transplanted with EPCs demonstrated increased protein expression of cyclooxygenase-2 and PGI 2 in adventitia, media, and endothelium. Furthermore, production of PGI 2 and arterial content of cAMP, second messenger for PGI 2 , were significantly augmented after transplantation of EPCs. In contrast, production of thromboxane A 2 was significantly reduced, whereas production of prostaglandin E 2 remained unchanged. The increased production of PGI 2 and arterial content of cAMP were inhibited only by a selective cyclooxygenase-2 inhibitor, NS-398. In vitro or in vivo treatment of basilar artery with conditioned media from EPCs also caused increase in cyclooxygenase-2 and PGI 2 synthase protein expression associated with elevation of cAMP. Our results suggest that in cerebral arteries, paracrine effect of EPCs promotes vasoprotection by increasing PGI 2 production and intracellular concentration of cAMP. This effect appears to be mediated by activation of arachidonic acid metabolism via stimulation of cyclooxygenase-2/PGI 2 synthase pathway.

Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio

“…The production of VEGF, which plays an important role in neoangiogenesis, is induced by PGI2 60) . The biosynthesis of PGI2 in endothelial cells is promoted by VEGF 61) , and EPCs promote the production of PGI2 by endothelial cells 62) . In contrast, TXA2 receptor (TP) stimulation restricts neoangiogenesis by inhibiting the effects of VEGF 63) .…”

Prostaglandin I 2 Promotes Recruitment of Endothelial Progenitor Cells and Limits Vascular Remodeling

“…Furthermore, circulatory EPCs stimulated PGI 2 production by endothelial cells in a paracrine fashion. 28 Taken together, the PGI 2 -IP system inherent in EPCs would work in an autocrineparacrine fashion, modulating the function of EPCs themselves. However, COX-2 is induced in activated endothelial and inflammatory cells, 26 and much of systemic PGI 2 is produced in a COX-2-dependent manner, 29 indicating that PGI 2 produced through multiple pathways would affect the function of EPCs.…”

Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia

“…Endothelial turnover can be facilitated through migration and proliferation of neighboring endothelial cells, although the rate of endothelial-cell proliferation in arteries is relatively low [19]. In contrast, EPCs rapidly repopulate denuded arteries, associated with an immediate improvement of endothelial function [20]. Thus in addition to their role in neovascularization, Urao et al were the first to demonstrate that EPO does not only induce EPCs mobilization but also promotes incorporation of EPCs into sites of endothelial injury [12].…”