Mechanisms Underlying Vascular Aging

血管疾病随着年龄的增长而增加，是老年人死亡的主要原因 人口。就心血管系统而言，血管老化最显著的特征是 血管壁逐渐变硬。的确，与年龄相关的主动脉僵硬可发生在 没有任何心血管危险因素，并早于收缩期高血压和 心血管疾病。因此，衰老过程本身是血管僵硬的重要危险因素。这个 与年龄相关的血管硬化的发病机制是血管壁不顺应性的丧失或 弹性蛋白纤维断裂，非顺应性胶原纤维沉积，内皮功能障碍 血管张力增加。这会导致进行性微血管功能障碍和系统性 高血压。影响血管壁顺应性和可缩性的信号通路，因此， 可能是血管老化或僵硬的重要致病因素。因为SMC是 导管动脉管壁中的优势细胞类型，随着年龄的增长而变硬，SMC功能异常将 可能在调节血管老化的力学和形态特征方面起着中心作用。 事实上，生理和病理研究表明，SMC的表型和功能至关重要 决定血管壁被动和主动生物力学特性的因素。因此，我们将重点关注 论岩石在SMC中的作用，并确定SMC岩石在调解中是否必要和/或充分 动脉硬化，如果是这样的话，确定相关的机制。 具体目标1将研究岩石对血管老化的SMC特异性影响。假说 有待检验的是，岩石在调节与年龄相关的血管僵硬方面是必要的，也是充分的。对于损失- 在功能研究方面，我们将产生SMC特异性的ROCK1-/-和ROCK2-/-小鼠(smROCK1-/-和 SmROCK2-/-)使用smSMC-CreERT2小鼠和条件性ROCK1/2FLOX/FLOX小鼠。对于功能增益研究， 我们将用smSMC-CreERT2小鼠和条件性caCKflx/flx小鼠产生SMC特异性caROCK小鼠。 此外，我们将确定人类增龄的共病，如肥胖和/或 动脉粥样硬化可激活SMC-ROCK，加速血管衰老。 特异性目标2将研究eEF1a和SRF磷酸化在介导 岩石对血管老化的下游影响。需要检验的假设是，磷酸化的 EEF1a和SRF by ROCK介导收缩和非收缩SMC功能，这些功能有助于 血管老化。具体地说，我们将1)确定SMC eEF1A和SRF的磷酸化是否增加 随着年龄的增长，2)产生了突变的eEF1a和SRF小鼠，以及3)决定了eEF1a和SRF 磷酸化有助于ROCK介导的血管改变，这些改变与主动脉硬化有关。

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.