Abstract 1476: Hypertension Hampers Bone-Marrow Mononuclear Cells Pro-Angiogenic Potential: Role of Angiotensin II-Related Pathways
Coronary risk factors are associated with reduction in both the number and function of bone marrow-derived endothelial progenitor cells. We hypothesized that hypertension, a major risk factor, may hamper bone-marrow derived mononuclear cells (BM-MNC) pro-angiogenic potential, leading to peripheral vascular disease. Ischemia was induced by right femoral artery ligation in Wistar Kyoto rats (WKY) or Spontaneously Hypertensive Rats (SHR) treated with or without angiotensin II type 1 receptor (AT1R) blocker (losartan, 30 mg/kg/day). Basal postischemic neovascularization was reduced in SHR compared to WKY (p<0.05, n=7). Treatment with AT1R blocker reduced blood pressure levels by 30% (p<0.05) and restored vessel growth in SHR to WKY levels. Interestingly, 14 days after cells transplantation, angiography scores (assessed by microangiography) and foot perfusion (evaluated by laser Doppler imaging) were decreased by 1.3- and 1.4-fold, respectively in WKY treated with BM-MNC isolated from SHR compared to those receiving BM-MNC isolated from WKY (p<0.05, n=6 per group). Alteration in BM-MNC pro-angiogenic potential was likely related to the reduction in their ability to differentiate into endothelial progenitor cells in vitro, as revealed by the 90% reduction in numbers of DilLDL/BS1lectin positive cells (p<0.001). Reactive oxygen species (ROS) levels were also increased by 2.2-fold in SHR BM-MNC compared to WKY BM-MNC (p<0.01), as assessed by L-012 luminescence. Co-treatment with AT1R blocker or antioxydants (NAC 3mM, apocynin 200°M) reduced ROS levels, improved the number of DilLDL/BS1lectin-positive cells by around 50% (p<0.05 versus untreated BM-MNC isolated from SHR) and restored BM-MNC pro-angiogenic effects in ischemic hindlimb to levels observed after transplantation of WKY BM-MNC. In conclusion, hypertension-induced angiotensin II dependent-increase in oxidative stress blunted progenitor cells pro-angiogenic function. Given the important role of bone marrow-derived endothelial progenitor cells for neovascularization of ischemic tissue, the decrease of BM-MNC activity may contribute to impaired vascularization in the setting of hypertension.