Molecular mechanisms of aortic wall remodeling in response to hypertension

Objective: The molecular basis of vascular response to hypertension is larg ely unknown. Both cellular and extracellular components are critical. In th e current study we tested the hypothesis that there is a balance between va scular cell proliferation and cell death during vessel remodeling in respon se 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 wa s 1 and 3 days and 1, 2, and 4 weeks for the study of the proximal aorta. R ibonuclease protection assay and Western blot analysis were used to evaluat e gene expression of growth and apoptosis-related cytokines with two sets o f 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 perfor med 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 ant i protein levels of transforming growth factor (TGF)-<beta>1 and TGF-beta3 were increased (P < .005 vs controls). Messenger RNA and protein of Bcl-xS and Fns ligand, known as proapoptotic factors, were both reduced after coar ctation (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 ch anges 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 TG F-<beta> and downregulation of Bcl-xS and Fas ligand gene expression. These findings suggest that a coordinated regulation of cell proliferation and c ell death contributes to arterial remodeling in response to acute sustained elevation of blood pressure. Cell proliferation precedes apoptosis by 2 we eks in this procedure.