Abnormalities of lipid metabolism, hypertension and angiogenesis have all been shown to play a role in the development and growth of atherosclerotic plaques. Angiotensin II has been shown to induce hypertension, and atherosclerosis in vivo and VEGF and angiogenesis in vitro. Preliminary data demonstrate that HMGCoA reductase inhibitors interfere with angiogenesis by inhibiting the angiogenic response to VEGF and FGF-2 in animal models for angiogenesis. Furthermore HMGCoA reductase inhibitors inhibit the formation of capillary-like structures by HUVECs cultured on Matrigel and the formation of tubes by human dermal epithelial cells cultured on a collagen gel. Finally they interfere with VEGF stimulated phosphorylation of VEGF receptors and angiotensin II induction of VEGF expression in HUVECs by inhibiting the posttranslational lipidation of a member of the Rho family of GTPases. The applicant will test 3 hypotheses: 1) using adenoviral vectors expressing mutant Rho GTPases, the applicant will test the hypothesis that angiogenesis is inhibited by HMGCoA reductase inhibitors and regulated by a specific member of the Rho family of GTPases; 2) that VEGF signaling is Rho dependent and inhibited by HMGCoA reductase inhibitors and that angiotensin II, FAK and hypoxia each stimulate angiogenesis and potentiate VEGF signaling via an effect on a common Rho dependent downstream kinase which is inhibited by HMGCoA reductase inhibitors and 3) that HMGCoA reductase inhibitors interfere with the expression of VEGF and VEGF receptors and decrease the neovascularization and the size of atherosclerotic plaques in cholesterol fed and angiotensin II treated Apo-E-/- mice. These studies would support the existence of a new relationship between lipid metabolism, growth factor signaling and hypertension which could have important implications for the treatment of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL066467-02
Application #
6778995
Study Section
Pathology A Study Section (PTHA)
Project Start
2002-09-30
Project End
2006-08-31
Budget Start
2003-05-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$185,453
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
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Higashimori, Mie; Tatro, Jeffrey B; Moore, Kathryn J et al. (2011) Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 31:50-7
Zhang, Yali; Naggar, Jack C; Welzig, C Michael et al. (2009) Simvastatin inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice: possible role of ERK. Arterioscler Thromb Vasc Biol 29:1764-71