Pkd2+l- vascular smooth muscles develop exaggerated vasocontraction in response to phenylephrine stimulation

Qi Qian, Larry W. Hunter, Hui Du, Qun Ren, Young Han, Gary C. Sieck

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Vascular complications are the leading cause of morbidity and mortality in autosomal dominant polycystic kidney disease. Although evidence suggests an abnormal vascular reactivity, contractile function in Pkd mutant vessels has not been studied previously. Contractile response to phenylephrine (PE; 10 -10 to 10-4M), an α1-adrenergic receptor agonist, was examined. De-endothelialized Pkd2+/- aortic rings generated a higher maximum force (Fmax) than that in wild-type (wt; 5.78 ± 0.73 versus 2.69 ± 0.43 mN; P < 0.001) and a significant left shift in PE dosage-response curve. On simultaneous recordings, Pkd2+/- aortic helical strips also responded to PE with a greater Fmax but a lesser [Ca2+]i rise, resulting in a greatly enhanced Δforce/ΔCa2+ ratio than that in wt. At Fmax, a higher elevation in the phosphorylated regulatory myosin light chain was observed in Pkd2+/- strips. Ca2+-dependent calmodulin/myosin light-chain kinase-mediated contraction was examined by direct Ca2+ (pCa8-5) stimulation to β-escin permeabilized aortic strips; the pCa-force curve in Pkd2+/- strips was not shifted, thereby indicating that PE induced dosage-response alteration that resulted from Ca2+-independent mechanisms. Quantitative analyses of contractile proteins demonstrated elevated expressions in smooth muscle α-actin and myosin heavy chain in Pkd2+/- arteries, changes that likely contribute to the higher Fmax. Similar to those in aortas, de-endothelialized Pkd2+/- resistance (fourth-order mesenteric) arteries responded to PE with a stronger contraction but a lesser [Ca 2+]i rise than in wt. Taken together, the arterial vasculature in Pkd2+/- mice exhibits an exaggerated contractile response and increased sensitivity to PE. An enhanced Ca2+- independent force generation and elevated contractile protein expression likely contribute to these abnormalities.

Original languageEnglish (US)
Pages (from-to)485-493
Number of pages9
JournalJournal of the American Society of Nephrology
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Nephrology

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