Hypertension is one of the most common age associated chronic disorders in human and affects more than 1 billion people worldwide. Despite intense research efforts over several decades, there is still no consensus on the primary causes of this disorder and its treatment is considered mandatory. We found previously that aortic vascular smooth muscle cells (VSMCs) stiffness contributes to the increased aortic stiffness in both aging and hypertension. Our recent studies demonstrated that increased VSMC stiffness is highly associated with an upregulation of serum response factor (SRF), a master transcription factor involved in orchestrating various programs of muscle gene expression. Pharmaceutical inhibition of SRF significantly reduces VSMC stiffness and also effectively rectifies aortic stiffening and high BP in adult hypertensive rats. These findings strongly suggest that SRF is a crucial mediator of aortic VSMC stiffness and a potential novel therapeutic target for hypertensive 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 our newly findings, we hypothesized that abnormal activation of SRF signaling in VSMCs from the aorta exclusively is a key mechanism of aging-induced aortic stiffening; and that manipulating this signaling pathway can decelerate aging-induced aortic stiffening and prevent the development of hypertension in the elderly. We will test our central hypothesis by a series of experiments under the following two specific aims.
In Aim 1, we will determine the physiological relevance of SRF signaling in aortic stiffening during aging and the impact on the development of hypertension in aged animals. By using different aging and hypertensive rat models, we will combine in vivo, ex vivo and in vitro measurements to determine the correlation between the SRF activation and the pathophysiological alterations in aortic stiffness and blood pressure (1A), and its aging dependency (1B). We will also test the effect of pharmacological inhibition of SRF on aging-induced aortic stiffening and hypertension (1C).
In Aim 2, we will elucidate the mechanisms by which SRF mediates aortic stiffening and hypertension in aging. We will use gain- and loss-of-function strategies to test the gene network regulated by SRF in isolated aortic VSMCs (2A) and determine SRF-mediated cellular mechanisms in age? induced aortic stiffness (2B), by combining a series of complementary bioengineering techniques including new developed advancing devices with atomic force microscopy and 3D reconstituted tissue models. We will also take the advantages of human induced pluripotent stem cell (iPSC)-derived VSMCs to explore the translational potential of our findings in aging-induced aortic stiffness in human cell-based models (2C). Based on our previous publications and extensive preliminary studies, we strongly believe that our proposed studies will elucidate the specific mechanisms involved in the age-induced aortic stiffness, which will provide a new strategy for preventing and treating aging related hypertension.
Lay abstract Hypertension is one of the most common age related chronic disorder in humans and is a well?established risk factor for stroke and cardiovascular diseases among older people. Less is known about the mechanisms involved in the aging large arteries. A key feature of the current proposal is to determine the alterations occurring in aortic stiffness during aging due to the novel hypothesis, that a key intrinsic component of aortic vascular smooth muscle cells (VSMCs) is regulated by the master transcription factor serum response factor. By combining physiological measurements in animal models with a series of novel bio-engineering techniques including atomic force microscopy and a reconstituted tissue model as well as a spatially distinct blood vessel model, we will identify the function of SRF in intrinsic VSMC stiffness during aging and as hypertension develops in aged animals. Once this is demonstrated, it will open up new avenues of therapy for aortic stiffness and hypertension in elderly, i.e., with pharmaceutical targets directed at the level of the VSMC itself.
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