RSK2 deletion alters vascular function and hypertension in resistance mesenteric arteries of aged mice
Authors: Ayon Ramon , Wang Yves , Kalra Jaspreet , Markowska Zaneta , Mathur Vaishnavi , Sonkusare Swapnil , Le Thu , Somlyo Avril 
Published: May 2023

Hypertension (HT), a condition that becomes increasingly prevalent with age, affects millions of Americans, and can lead to heart disease, stroke, and kidney failure. Pathophysiological mechanisms contributing to the increased peripheral vascular resistance associated with HT, include arterial remodeling, increased vascular contraction and reduced vasodilation. Vascular structural and functional changes of aging closely resemble the classical HT phenotype. Current antihypertensive medications are less than 50% effective at controlling blood pressure, highlighting the need for better therapeutic options. Recently, our group has demonstrated that p90 ribosomal s6 kinase (Rsk2) plays a significant physiological role in SM contractility. We have shown that young adult global Rsk2 KO mice had more dilated mesenteric arteries (MAs), with reduced vessel tone, stiffness and RLC20 phosphorylation, and significantly lower basal blood pressure compared to WT. However, it is unknown whether Rsk2 plays a functional role in age-related HT. We found that >24-month-old WT mice had a significantly higher mortality rate compared to aged-match Rsk2 KO. Baseline Systolic blood pressure (SBP) was significantly lower in KOs compared to WT. L-NAME elevated SBP in WT but not in KO mice. There were no differences in echo parameters in WT and Rsk2 KO aged mice. Histology of 3rd and 4th order WT and Rsk2 KO MA cross-sections revealed no differences in lumen diameter, wall, thickness, or ratio of wall area to total area in aged mice. Thus, Rsk2 deletion did not alter vascular remodeling in resistance arteries of aged mice. Pressure myography studies assessed vascular reactivity and arterial stiffness in MAs isolated from Rsk2 KO and WT mice. Myogenic tone was significantly lower in Rsk2 KO 3rd and 4th order resistance arteries. Vascular stiffness, in aged WT and aged Rsk2 KO mice did not differ but was significantly increased when compared to young WT mice. Resistance MAs (<200 μm) from young and aged WT mice were examined for Ca2+ signals, and relaxation to spermine NONOate after 88 wk of age. Arteries from aged mice experienced an attenuated vasodilatory response to the NO donor at 1 and 3 μM when compared to arteries from young mice. Spontaneous Ca2+ frequency was significantly increased in aged mice compared to young mice. Ca2+ frequency in young mice was attenuated by the RSK inhibitor LJH685 (5 μM), but unchanged in aged mice. The mean Ca2+ amplitude in MAs from aged mice was significantly upregulated when compared to young mice, and significantly attenuated by LJH685 in both young and aged arteries. Our data suggest that in the absence of Rsk2, vessel remodeling and changes in BP are dissociated in aged mice. Furthermore, we have shown that Rsk2 serves as a mediator of downstream signaling elements that alter vascular function in aged mice by decreasing NO sensitivity and enhancing [Ca2+]i resulting in an increase in vascular tone that contributes to HT. NIH grant for AVS: HL147555; Research Supplements for RJA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.