Mechanisms Underlying Vascular Aging

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Vascular disease increases with advancing age and is the leading cause of death in the elderly population. The most prominent feature of vascular aging with respect to the cardiovascular system is the gradual and progressive stiffening of the vessel wall. Indeed, age-related aortic stiffness can occur in the absence of any cardiovascular risk factors, and antedates the development of systolic hypertension and cardiovascular disease. Thus, the aging process itself is an important risk factor for vascular stiffness. The pathogenesis of age-related vascular stiffening is marked by non-compliance of the vessel wall due to loss or fragmentation of elastin fibers, deposition of non-compliant collagen fibers, endothelial dysfunction, and increased vascular tone. This leads to progressive microvascular dysfunction and the development of systemic hypertension. Signaling pathways, which affect the compliance and contractility of the vessel wall, therefore, may be important contributors to the pathogenesis of vascular aging or stiffening. Because SMCs are the predominant cell type in the vessel wall of conduit arteries that stiffens with age, abnormal SMC function will probably play a central role in mediating the mechanical and morphological properties of vascular aging. Indeed, physiological and pathological studies suggest that SMC phenotype and function are critical determinants of both passive and active biomechanical properties of the vessel wall. Accordingly, we will focus on the role of ROCK in SMC and determine whether SMC ROCKs are necessary and/or sufficient in mediating arterial stiffening, and if so, to determine the relevant mechanisms involved. Specific aim 1 will investigate the SMC-specific effects of ROCKs on vascular aging. The hypothesis to be tested is that ROCKs are necessary and sufficient in mediating age-related vascular stiffening. For loss- of-function studies, we will generate SMC-specific ROCK1–/– and ROCK2–/– mice (smROCK1–/– and smROCK2–/–) using smSMC-CreERT2 mice and conditional ROCK1/2flox/flox mice. For gain-of-function studies, we will generate SMC-specific caROCK mice using smSMC-CreERT2 mice and conditional caROCKflox/flox mice. In addition, we will determine whether co-morbidities of advancing age in humans such as obesity and/or atherosclerosis can activate SMC ROCK to accelerate the vascular aging. Specific aim 2 will investigate the role of eEF1A and SRF phosphorylation in mediating the downstream effects of ROCKs on vascular aging. The hypothesis to be tested is that phosphorylation of eEF1A and SRF by ROCK mediates both contractile and non-contractile SMC functions that contribute to vascular aging. Specifically, we will 1) determine whether SMC eEF1A and SRF phosphorylation increases with age, 2) develop phosphor-mutant eEF1A and SRF mice, and 3) determine whether eEF1A and SRF phosphorylation contributes to ROCK-mediated vascular changes that are associated with aortic stiffening.