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Loss of function RGS2 mutations augment vascular contractility ex vivo
Author(s) -
Phan Hoa Thi Nhu,
Jackson William,
Neubig Richard
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.699.2
Subject(s) - rgs2 , medicine , endocrinology , regulator of g protein signaling , phenylephrine , biology , chemistry , g protein , blood pressure , gtpase activating protein , receptor
Objective Regulator of G protein signaling 2 (RGS2) plays a significant role in alleviating vascular contraction and promoting vascular relaxation due to its GTPase accelerating protein activity toward Gαq. Through a cell‐based Ca 2+ mobilization assay, we identified 4 loss‐of‐function (LOF) mutations (Q2L, D40Y, R44H and R188H) out of 16 rare, missense mutations in RGS2 selected from various human exome sequencing projects. This study is to investigate whether these LOF RGS2 mutations disrupt the protein function in regulating vascular contractility . Approach and result We confirmed that RGS2‐deficient mice expressed a hypertensive phenotype by telemetric femoral artery blood pressure measurement in conscious mice (WT SBP 120 ± 3 vs RGS2 −/− SBP 128 ± 2 mmHg, p<0.01) . Isolated mesenteric arteries from RGS2 −/− mice showed higher contractile response to 10 nM angiotensin II (AngII) stimulation in pressure myograph while isolated aortic rings from those animals generated more tension upon phenylephrine (PE) stimulation (Emax 238 mg vs 68 mg, p = 0.01) compared to aortic rings from RGS2 +/+ mice. Reintroduction of wild‐type RGS2‐GFP plasmids into RGS2 −/− mesenteric arteries by reversible permeabilization suppressed the vasoconstrictor response to 50 nM AngII (RGS2 WT plasmid −4% vs pcDNA control −35% of basal diameter, p = 0.01). Transfection with RGS2 LOF mutation plasmidss did not suppress Ang II constriction compared to those expressing WT‐RGS2 (Q2L −20%, D40Y, R44H and R188H −30% of basal diameter, p < 0.05) . Conclusions This study is the first to investigate the function of human mutant RGS2 in resistance arteries in a near physiological condition. It demonstrates that RGS2 attenuates vasoconstriction in the mesenteric arteries and that RGS2 mutations disrupt this effect. Although these mutations are rare, knowledge about their function may provide insights into pathophysiology and treatment. Support or Funding Information This work was supported by the American Heart Association predoctoral fellowship [15PRE24680004] to H.P). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .