RGS5/16-dependent phenotype regulation of arterial vascular smooth muscle cells

• Applicant: Professor Dr. Thomas Korff, since 3/2020
• Subject Area: Anatomy and Physiology ; Pharmacology ; Cell Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413605646

A pivotal feature of arteries is their capacity to adapt the architecture of the vascular wall to alterations in the microenvironment. For instance, a chronic increase in blood flow promotes arterial dilation while elevated blood pressure (hypertension) results in thickening and stiffening of the arterial wall. The latter is in fact a main risk factor for cardiovascular diseases including myocardial infarction or stroke. This microenvironment-dependent structural arterial remodeling is caused by activation of medial vascular smooth muscle cells (VSMCs) triggered by biomechanical or neurohumoral stimuli. In this context, G protein activity and signaling is a limiting factor for signal transduction of both kinds of stimuli to orchestrate phenotype changes of arterial VSMCs. G-protein activity itself is controlled by an endogenous protein family known as “regulators of G-protein signaling” (RGS). We have previously shown that biomechanical stimulation of VSMCs was sufficient to increase cytoplasmic abundance of RGS5 which was required for RhoA activation – a critical determinant of the VSMC phenotype during biomechanically-induced arterial remodeling processes. Likewise, loss of RGS5 in vivo prevented both flow-induced (arteriogenesis) as well as hypertension-induced arterial remodeling in mice as well as RhoA activation. RGS5 is an endogenous inhibitor of Gαq/11 and Gαi/o signaling and hence appears to be crucial for activation of RhoA. Moreover, recent results suggested that loss of RGS5 unleashes Gαq/11-dependent PKC activity which subsequently inhibited RhoA activation. Furthermore, hypertension also induced RGS16 expression – a functional homologue to RGS5 – which was further increased in the absence of RGS5. Interestingly, RGS5 and RGS16 both have the ability to inhibit Gαq/11 and Gαi/o subunits but differ in their affinity. Collectively, based on our findings we hypothesize that RGS5 is essential to balance G-protein-mediated signals. This seems to be a prerequisite to attenuate the Gαq/11-PKC- signaling axis which promotes RhoA-dependent activation of arterial VSMCs exposed to biomechanical stress. Consequently, this project aims at (1) characterizing the impact of VSMC-specific overexpression of RGS5 on arterial function and arterial remodeling processes as well as delineating the mechanism of RhoA activation in this context and (2) exploring the regulation and functional contribution of RGS16 to G-protein- and hypertension-induced VSMC responses and arterial remodeling.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Caroline Arnold, Ph.D., until 3/2020