Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY: Increasing prevalence and regressing control of the common comorbidities obesity and hypertension pose a growing threat to human health, but targeted therapies specific to obesity-associated hypertension (65-78% of primary hypertension cases) are not yet developed. Aortic stiffness is a hallmark in both obesity and hypertension. Since obesity is marked by a pathological increase in visceral fat, the role of adipokines, substances made in the fat, must be investigated. Intriguingly, the novel adipokine chemerin is largely pro-hypertensive, and chemerin is positively associated with aortic stiffness. Recently, we discovered that chemerin is resident to the medial smooth muscle cells as well as perivascular adipose tissue (PVAT) of the vasculature with functional consequence. Chemerin is a direct vasoconstrictor in rat and human vessels through the receptor Chemerin1, and inhibition of Chemerin1 results in a loss of basal (uncontracted) vessel tone. Use of antisense oligonucleotides (ASOs) that prevent chemerin translation reveal chemerin’s importance in supporting adiposity-associated hypertension: the ASO against chemerin reduced blood pressure of male and female Dahl SS rats made hypertensive by a high fat diet by over 30 mmHg vs ASO control. Taken together, these data suggest that chemerin is an important regulator of blood vessel function and overall blood pressure through activity at the vasculature. Therefore, the overall hypothesis of this proposal is that chemerin resident to the vasculature acts locally to influence blood vessel function, blood pressure, and vessel stiffness. A range of experimental approaches will be used, including isometric contractility to investigate tunica-specific contributions of endogenous chemerin; RNAscope® and immunohistochemistry to visualize vascular chemerin expression; use of CCX832 to antagonize chemerin’s predominant biological receptor Chemerin1; radiotelemetry to measure blood pressure; high frequency ultrasound imaging to measure aortic stiffness; and use of a newly created chemerin KO rat on the Dahl SS background. Aim 1 tests the hypothesis that chemerin is resident to the vasculature and supports basal blood vessel function. Aim 2 tests the hypothesis that vascular chemerin drives adiposity-associated hypertension and vascular stiffening. The proposed work will elucidate the mechanistic contributions of chemerin in supporting healthy blood pressure and driving adiposity-associated hypertension and vascular stiffness. Understanding chemerin’s role in blood pressure regulation and pathology provides the essential groundwork to elevate chemerin as a therapeutic target for obesity-associated hypertension, and completion of the proposed studies allows the applicant to develop the necessary skills and rigorous training necessary for success as an independent and collaborative clinical industrial scientist.
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