TY - JOUR
T1 - Pkd2+l- vascular smooth muscles develop exaggerated vasocontraction in response to phenylephrine stimulation
AU - Qian, Qi
AU - Hunter, Larry W.
AU - Du, Hui
AU - Ren, Qun
AU - Han, Young
AU - Sieck, Gary C.
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2006050501
DO - 10.1681/ASN.2006050501
M3 - Article
C2 - 17202419
AN - SCOPUS:33846674526
SN - 1046-6673
VL - 18
SP - 485
EP - 493
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 2
ER -