Dehidroepiandrostenedione modulates cellular events involved in vascular repair

Abstract

In recent years dehidroepiandrostenedione(DHEA) has emerged as a promising alternative for hormone replacement therapydue to its ability to act as a precursor for local formation of activesteroids. Maintenance of vascular health depends mainly on the prevention of vascular injury and thepromotion of vessel remodeling (angiogenesis). Endothelial cells (EC) migrationand proliferation, and the expression of endothelial factors that en-hance ECadhesion to subendothelium (uPA and tPA) are crucial events in new vesselformation. In this study we evaluated the effects of DHEA on processes involvedin the initiation of vascular lesions (platelet adhesion and aggregation) andin angiogenesis. We demonstrated that EC treatment with 20nM DHEA produces aninhibition on platelet adhesion to endothelium (24h - 25%below Cont p<0.05),and decreases endothelium dependent platelet aggregation (60min - 15%below contp<0.05) in a nitric oxide dependent manner, since preincubation with NAMEannulated this effect (p<0.01). EC proliferation studies (MTT assay) showed that24h treatment with DHEA stimulates cell growth (32, 22 and 12% above Cont 2, 20and 200nM DHEA p<0.05). Indeed, using wound healing assays, we found thatthe steroid also promotes cell motility (9±2, 25±8 Cont, 20nM DHEA migratingcells/field p<0.01). The expression of uPA, tPA and androgen receptor (AR) wasmeasured by inmunoblot. To that end, EC were treated for 12 to 48h with 20 or200nM DHEA. The steroid enhances the expres-sion of both factors (30-80% abovecontrol p<0.05). The androgen receptor expression was also increased,suggesting that DHEA mechanism of action could involve AR. Finally, in rataortic ring angiogenesis assays, we observed that DHEA treatment promotes ECsprouting and capillary like tube formation (30% above control, p<0.05). Thepresented results show that DHEA exerts a direct action on EC, contributing tothe prevention of vascular injury and promoting angiogenesis.