One of the major unanswered questions in hypertension research is the mechanism of vascular hypertrophy. It has been proposed that this structural adaptation of the blood vessel may play an important role in reducing arterial wall tension and in amplifying hypertension. The factors that initiate and maintain blood vessel hypertrophy have not been fully elucidated. Since angiotensin has been shown to induce a growth response in cultured vascular smooth muscle cells (VSMC), we hypothesize that during the development of chronic hypertension, the local production of angiotensin may be responsible for the hypertrophic response of the blood vessel. To examine this possibility, the vascular wall renin angiotensin system will be characterized and the level of renin and angiotensinogen mRNA expressions will be determined. To link vascular angiotensin activation with vascular hypertrophy, the effects of converting enzyme inhibitor (or angiotensin antagonist) vs nonspecific vasodilator (hydralazine) (titrated to comparable blood pressure reduction) on vascular hypertrophy will be compared. This will allow one to examine whether angiotensin is responsible for the increased blood vessel mass in hypertension. In order to understand the molecular mechanism of angiotensin induced hypertrophy, its effect on c-fos and PDGF expressions will be studied. We propose to study c-fos based on the recent data that AII stimulated c-fos mRNA in VSMC and that c-fos is important in 3T3 fibroblast growth and proliferation. The transcriptional regulation of the c-fos gene including the elements responsible for AII responsiveness will be examined in detail. Documentation of the importance of this mechanism on VSMC growth will be carried out by blocking c-fos mRNA using a c-fos antisense expression vector. To examine the contribution of PDGF expression, we will also block PDGF expression using a PDGF antisense expression vector and determine the effect on VSMC growth and hypertrophy. In addition, the interaction of AII with other contractile agonists (e.g. norepinephrine) on vascular hypertrophy will be studied in hypertension. The above experiments should define the role of vascular angiotensin in the hypertrophy of blood vessels and provide insight into the molecular mechanism of this vascular hypertrophy.
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