Pravastatin ameliorate hypoxia-induced pulmonary hypertension by normalizing the mobilization and homing of progenitor cells

Abstract

We previously reported that BM-derived progenitor cells(PCs) contribute to the pulmonary arterial (PA) remodeling in hypoxia-induced pulmonary hypertension(PH). The mechanism for the PCs homing to the remodeling site is unknown. We hypothesized that the intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD11a/CD18, contribute to the homing of the BMPCs to the remodeling vasculature. We analyzed the number of circulating VEGFR2 + mononuclear cells and adhesion molecules on the cells with flow-cytometry. Mice were exposed to hypoxia (O 2 = 10%) for 5wks with or without pravastatin (2mg/kg/day). Both the right ventricular(RV) systolic pressure (RVSP) and RV/LV+ septum were higher in the hypoxic mice than in the normoxic mice (34 ± 3mmHg vs 21 ± 3mmHg and 0.37 ± 0.03 vs 0.25 ± 0.03, respectively, p < 0.01). The hypoxic mice with pravastatin resulted in a decline of PH (RVSP;28 ± 3mmHg, RV/LV + septum; 0.33 ± 0.02, p < 0.01). Flow-cytometry revealed that the number of VEGFR2 +cells was significantly increased and CD18/CD11a expression on the cells was enhanced in the hypoxic mice. Immunostaining demonstrated that BM-derived CD11a/CD18 positive cells were attached to the remodeled PA walls that express ICAM-1 strongly. Pravastatin reduced the number of VEGFR2 +cells and their CD18/CD11a expression and also the ICAM-1 expression on PA walls. In conclusion, hypoxia increased the circulating BM-derived VEGFR2 +cells, which might home to the remodeling vasculature with the aid of adhesive molecules. Furthermore, pravastatin might ameliorate hypoxia-induced PH partly by normalizing the mobilization and homing of PCs.