title: Pkd2+/- vascular smooth muscles develop exaggerated vasocontraction in response to phenylephrine stimulation.
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(-4)M), an alpha1-adrenergic receptor agonist, was examined. De-endothelialized Pkd2(+/-) aortic rings generated a higher maximum force (F(max)) 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 F(max) but a lesser [Ca(2+)](i) rise, resulting in a greatly enhanced Deltaforce/DeltaCa(2+) ratio than that in wt. At F(max), a higher elevation in the phosphorylated regulatory myosin light chain was observed in Pkd2(+/-) strips. Ca(2+)-dependent calmodulin/myosin light-chain kinase-mediated contraction was examined by direct Ca(2+) (pCa8-5) stimulation to beta-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 Ca(2+)-independent mechanisms. Quantitative analyses of contractile proteins demonstrated elevated expressions in smooth muscle alpha-actin and myosin heavy chain in Pkd2(+/-) arteries, changes that likely contribute to the higher F(max). 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 Ca(2+)-independent force generation and elevated contractile protein expression likely contribute to these abnormalities.
authors.affiliation: Department of Medicine and Physiology, Eisenberg S-24, Nephrology, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55905, USA. qian.qi@mayo.edu
authors.forename: Qi
authors.initials: Q
authors.lastname: Qian
authors.forename: Larry W
authors.initials: LW
authors.lastname: Hunter
authors.forename: Hui
authors.initials: H
authors.lastname: Du
authors.forename: Qun
authors.initials: Q
authors.lastname: Ren
authors.forename: Young
authors.initials: Y
authors.lastname: Han
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000502:physiology; D004928:Escin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology*; D050396:TRPP Cation Channels; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D002118:Calcium; D004928:Escin; D010656:Phenylephrine; D050396:TRPP Cation Channels