Molecular mechanisms of aortic wall remodeling in response to hypertension

Abstract

Objective: The molecular basis of vascular response to hypertension is largely unknown. Both cellular and extracellular components are critical. In the current study we tested the hypothesis that there is a balance between vascular cell proliferation and cell death during vessel remodeling in response to hypertension. Methods: A midthoracic aortic coarctation was created in rats to induce an elevation of blood pressure proximal to the coarctation. The time course was 1 and 3 days and 1, 2, and 4 weeks for the study of the proximal aorta. Ribonuclease protection assay and Western blot analysis were used to evaluate gene expression of growth and apoptosis-related cytokines with two sets of multiple probes, rCK-3 and rAPO-1. Cell proliferation was determined with BrdU (5-bromo -2′-deoxyuridine) incorporation. Apoptosis was examined with TUNEL (transferase-mediated dUTP nick end-labeling). Morphometry was performed on histologic sections. Results: Coarctation produced hypertension in the proximal aorta, 118 ± 9 mm Hg versus 94 ± 6 mm Hg in controls (P < .002). Both messenger RNA and protein levels of transforming growth factor (TGF)-β1 and TGF-β3 were increased (P < .005 vs controls). Messenger RNA and protein of Bcl-xS and Fas ligand, known as proapoptotic factors, were both reduced after coarctation (P < .005 vs controls). There was increased BrdU incorporation at 3 days and 1 and 2 weeks (P < .001 vs controls). There were no remarkable changes in the apoptosis rate until 4 weeks later. Conclusion: Cell proliferation was stimulated at 3 days, and apoptosis was halted until 4 weeks. These changes were associated with upregulation of TGF-β and downregulation of Bcl-xS and Fas ligand gene expression. These findings suggest that a coordinated regulation of cell proliferation and cell death contributes to arterial remodeling in response to acute sustained elevation of blood pressure. Cell proliferation precedes apoptosis by 2 weeks in this procedure.