Renovascular hypertension by two-kidney one-clip enhances endothelial progenitor cell mobilization in a p47phox-dependent manner.

Background: Enhanced mechanical forces, e.g. in arterial hypertension, stimulate the formation of reactive oxygen species (ROS) by the NAD(P)H oxidase. Since bone marrow derived endothelial progenitor cells (EPCs) contribute to vascular remodeling and repair, we investigated whether renovascular hypertension stimulates EPC mobilization in a NAD(P)H oxidase-dependent manner.

Methods: Renovascular hypertension was induced by two-kidney one-clip (2K1C) in C57BL/6 (WT) and in mice lacking the p47phox subunit of the NAD(P)H oxidase (p47phox-/-).

Results: In WT, 2K1C increased blood pressure levels by 32.4 +/- 4 mmHg, which was associated with a four-fold increase in circulating EPCs (Sca-1+;Flk-1+). In p47phox-/- mice, the increase in blood pressure was significantly reduced (15.1 +/- 1.8 mmHg, P < 0.05) and not associated with increased EPCs. Inhibitors of the renin-angiotensin system (RAS) and nonspecific vasodilators normalized blood pressure and inhibited EPC mobilization in WT mice after 2K1C. In addition, p47phox deficiency and pharmacological ROS blockage abrogated 2K1C-induced blood pressure elevation and EPC mobilization. Stromal cell derived factor (SDF)-1 and matrix metalloproteinase (MMP)-9 activity in the bone marrow, required for EPC mobilization, were modulated in WT mice after 2K1C. In contrast, no alterations in SDF-1 and MMP-9 were observed in p47phox-/- mice. Moreover, enhanced migration of Lin- bone marrow mononuclear cells was observed when stimulated with plasma from 2K1C WT mice but not when stimulated with plasma from 2K1C p47phox-/- mice.

Conclusion: Enhanced mechanical stretch in renovascular hypertension induces EPC mobilization in a p47phox-dependent manner, involving bone marrow SDF-1 and MMP-9 which may contribute to compensatory vascular adaptation in renovascular hypertension.