Received for publication September 12, 2007.
Revised February 27, 2008.
Accepted for publication February 27, 2008.

Combination of the angiotensin converting enzyme inhibitor Perindopril and the diuretic Indapamide activate post-natal vasculogenesis in Spontaneaously Hypertensive Rats

Abstract

Cardiovascular risk factors are associated with reduction in both the number and function of vascular progenitor cells. We hypothesized that i) hypertension abrogates post-natal vasculogenesis and ii) antihypertensive treatment based on the combination of Perindopril (angiotensin converting enzyme inhibitor) and Indapamide (diuretic) may counteract hypertension-induced alteration in progenitor cells-related effects. Post-ischemic neovascularization was significantly lower in untreated SHR when compared to WKY (p<0.05). Treatment of SHR with Perindopril and the combination of Perindopril/Indapamide reduced the blood pressure levels and normalized vessel growth in ischemic area. Co-treatment with Perindopril and Indapamide increased VEGF and eNOS protein contents, two key pro-angiogenic factors. Interestingly, 14 days after bone-marrow mononuclear cells (BM-MNC) transplantation, revascularization was significantly lower in ischemic SHR receiving BM-MNC isolated from SHR compared to those receiving BM-MNC isolated from WKY (p<0.05). Alteration in pro-angiogenic potential of SHR BM-MNC was likely related to the reduction in their ability to differentiate into endothelial progenitor cells in vitro. Furthermore, the number of circulating EPC was reduced by 3.1-fold in SHR when compared to WKY rats (p<0.001). Treatments with Perindopril or Perindopril/Indapamide restored the ability of BM-MNC to differentiate in vitro into EPC, increased the number of circulating EPC and reestablished BM-MNC pro-angiogenic effects. Therefore, hypertension is associated with a decrease in the number of circulating progenitor cells and in the BM-MNC pro-angiogenic potential, likely leading to vascular complications in this setting. Combination of Perindopril and Indapamide counteracts hypertension-induced alterations in progenitor cells-related effects and restores blood vessel growth.

Key words: ACE inhibitor, Angiogenesis, Diuretic, Hypertension, Ischemia, nitric oxide