Molecular mechanisms of aortic wall remodeling in response to hypertension.
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)-beta1 and TGF-beta3 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.


CONCLUSIONS
Cell proliferation was stimulated at 3 days, and apoptosis was halted until 4 weeks. These changes were associated with upregulation of TGF-beta 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.
Department of Surgery, Stanford University, California 94305-5642, USA. cx11@stanford.edu
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D000818:Animals; D001017:Aortic Coarctation / Q000473:pathology*; D016923:Cell Death / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000502:physiology; D006973:Hypertension / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein