PROJECT SUMMARYHypertension is one of the most common age associated chronic disorders in human and affects more than 1billion people worldwide. Despite intense research efforts over several decades there is still no consensus onthe primary causes of this disorder and its treatment is considered mandatory. We found previously that aorticvascular smooth muscle cells (VSMCs) stiffness contributes to the increased aortic stiffness in both aging andhypertension. Our recent studies demonstrated that increased VSMC stiffness is highly associated with anupregulation of serum response factor (SRF) a master transcription factor involved in orchestrating variousprograms of muscle gene expression. Pharmaceutical inhibition of SRF significantly reduces VSMC stiffnessand also effectively rectifies aortic stiffening and high BP in adult hypertensive rats. These findings stronglysuggest that SRF is a crucial mediator of aortic VSMC stiffness and a potential novel therapeutic target forhypertensive aortic stiffness. However the physiological significance of SRF in vascular aging and aging-related hypertension has not been established and the underlying mechanisms are unrevealed. Based on ournewly findings we hypothesized that abnormal activation of SRF signaling in VSMCs from the aortaexclusively is a key mechanism of aging-induced aortic stiffening; and that manipulating this signaling pathwaycan decelerate aging-induced aortic stiffening and prevent the development of hypertension in the elderly. Wewill test our central hypothesis by a series of experiments under the following two specific aims. In Aim 1 wewill determine the physiological relevance of SRF signaling in aortic stiffening during aging and the impact onthe development of hypertension in aged animals. By using different aging and hypertensive rat models wewill combine in vivo ex vivo and in vitro measurements to determine the correlation between the SRFactivation and the pathophysiological alterations in aortic stiffness and blood pressure (1A) and its agingdependency (1B). We will also test the effect of pharmacological inhibition of SRF on aging-induced aorticstiffening and hypertension (1C). In Aim 2 we will elucidate the mechanisms by which SRF mediates aorticstiffening and hypertension in aging. We will use gain- and loss-of-function strategies to test the gene networkregulated by SRF in isolated aortic VSMCs (2A) and determine SRF-mediated cellular mechanisms in ageinduced aortic stiffness (2B) by combining a series of complementary bioengineering techniques includingnew developed advancing devices with atomic force microscopy and 3D reconstituted tissue models. We willalso take the advantages of human induced pluripotent stem cell (iPSC)-derived VSMCs to explore thetranslational potential of our findings in aging-induced aortic stiffness in human cell-based models (2C). Basedon our previous publications and extensive preliminary studies we strongly believe that our proposed studieswill elucidate the specific mechanisms involved in the age-induced aortic stiffness which will provide a newstrategy for preventing and treating aging related hypertension.