Ben Ma1,2, Elaina Melton1, Robert Wiener3, Ning Zhou2, Wenqian Wu1, Lo Lai1, Charles Wang4, Kevin D Costa3, Hongyu Qiu1,2. 1. Center for Molecular and Translational Medicine, Institute of Biomedical Sciences, Georgia State University, Atlanta, GA (B.M., E.M., W.W., L.L., H.Q.). 2. Division of Physiology, Department of Basic Sciences (B.M., N.Z., H.Q.), School of Medicine, Loma Linda University, CA. 3. Department of Medicine (Cardiology), Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY (R.W., K.D.C.). 4. Department of Basic Sciences & Center for Genomics (C.W.), School of Medicine, Loma Linda University, CA.
Abstract
BACKGROUND: Aortic stiffening is strongly associated with both aging and hypertension, but the underlying mechanisms remain unclear. We hypothesized that aging-induced aortic stiffness is mediated by a mechanism differing from hypertension. METHODS: We conducted comprehensive in vivo and in vitro experiments using multiple rat models to dissect the different mechanisms of aortic stiffening mediated by aging and hypertension. RESULTS: A time-course study in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive rats showed more pronounced aging-associated aortic stiffening in SHR versus WKY. Angiotensin II-induced hypertension was associated with more significant aortic stiffening in older versus young WKY rats. Hypertension aggravated aging effects on aortic wall thickness and extracellular matrix content, indicating combinational effects of aging and hypertension on aortic stiffening. Intrinsic stiffness of isolated aortic vascular smooth muscle cells (VSMCs) increased with age in WKY rats, although no significant difference between older SHR and older WKY VSMCs was observed in 2-dimensional culture, reconstituted 3-dimensional tissues were stiffer for older SHR versus older WKY. A selective inhibitor that reduced hypertension-mediated aortic stiffening did not decrease age-related stiffening in aortic VSMCs and aortic wall. Integrin β1 and SM22 (smooth muscle-specific SM22 protein) expression were negligibly changed in WKY VSMCs during aging but were markedly increased by hypertension in older versus young WKY VSMCs. A notable shift of filamin isoforms from B to A was detected in older WKY VSMCs. CONCLUSIONS: Our results indicate distinct mechanisms mediating aging-associated aortic VSMC and vessel stiffness, providing new insights into aortic stiffening and the pathogenesis of hypertension in the elderly.
BACKGROUND: Aortic stiffening is strongly associated with both aging and hypertension, but the underlying mechanisms remain unclear. We hypothesized that aging-induced aortic stiffness is mediated by a mechanism differing from hypertension. METHODS: We conducted comprehensive in vivo and in vitro experiments using multiple rat models to dissect the different mechanisms of aortic stiffening mediated by aging and hypertension. RESULTS: A time-course study in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive rats showed more pronounced aging-associated aortic stiffening in SHR versus WKY. Angiotensin II-induced hypertension was associated with more significant aortic stiffening in older versus young WKY rats. Hypertension aggravated aging effects on aortic wall thickness and extracellular matrix content, indicating combinational effects of aging and hypertension on aortic stiffening. Intrinsic stiffness of isolated aortic vascular smooth muscle cells (VSMCs) increased with age in WKY rats, although no significant difference between older SHR and older WKY VSMCs was observed in 2-dimensional culture, reconstituted 3-dimensional tissues were stiffer for older SHR versus older WKY. A selective inhibitor that reduced hypertension-mediated aortic stiffening did not decrease age-related stiffening in aortic VSMCs and aortic wall. Integrin β1 and SM22 (smooth muscle-specific SM22 protein) expression were negligibly changed in WKY VSMCs during aging but were markedly increased by hypertension in older versus young WKY VSMCs. A notable shift of filamin isoforms from B to A was detected in older WKY VSMCs. CONCLUSIONS: Our results indicate distinct mechanisms mediating aging-associated aortic VSMC and vessel stiffness, providing new insights into aortic stiffening and the pathogenesis of hypertension in the elderly.
Authors: Olivia Gay; Benoît Gilquin; Fumihiko Nakamura; Zandra A Jenkins; Rosannah McCartney; Deborah Krakow; Alexandre Deshiere; Nicole Assard; John H Hartwig; Stephen P Robertson; Jacques Baudier Journal: Proc Natl Acad Sci U S A Date: 2011-06-27 Impact factor: 11.205
Authors: Hongyu Qiu; Yi Zhu; Zhe Sun; Jerome P Trzeciakowski; Meredith Gansner; Christophe Depre; Ranillo R G Resuello; Filipinas F Natividad; William C Hunter; Guy M Genin; Elliot L Elson; Dorothy E Vatner; Gerald A Meininger; Stephen F Vatner Journal: Circ Res Date: 2010-07-15 Impact factor: 17.367