title: Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension.
abstract: Vascular tone, an important determinant of systemic vascular resistance and thus blood pressure, is affected by vascular smooth muscle (VSM) contraction. Key signaling pathways for VSM contraction converge on phosphorylation of the regulatory light chain (RLC) of smooth muscle myosin. This phosphorylation is mediated by Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) but Ca(2+)-independent kinases may also contribute, particularly in sustained contractions. Signaling through MLCK has been indirectly implicated in maintenance of basal blood pressure, whereas signaling through RhoA has been implicated in salt-induced hypertension. In this report, we analyzed mice with smooth muscle-specific knockout of MLCK. Mesenteric artery segments isolated from smooth muscle-specific MLCK knockout mice (MLCK(SMKO)) had a significantly reduced contractile response to KCl and vasoconstrictors. The kinase knockout also markedly reduced RLC phosphorylation and developed force. We suggest that MLCK and its phosphorylation of RLC are required for tonic VSM contraction. MLCK(SMKO) mice exhibit significantly lower basal blood pressure and weaker responses to vasopressors. The elevated blood pressure in salt-induced hypertension is reduced below normotensive levels after MLCK attenuation. These results suggest that MLCK is necessary for both physiological and pathological blood pressure. MLCK(SMKO) mice may be a useful model of vascular failure and hypotension.
authors.affiliation: Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing, China.
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: He
authors.forename: Yan-Ning
authors.initials: YN
authors.lastname: Qiao
authors.forename: Cheng-Hai
authors.initials: CH
authors.lastname: Zhang
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Peng
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.forename: Yun-Qian
authors.initials: YQ
authors.lastname: Gao
authors.forename: Caiping
authors.initials: C
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Su
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Kamm
authors.forename: James T
authors.initials: JT
authors.lastname: Stull
authors.forename: Min-Sheng
authors.initials: MS
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D008638:Mesenteric Arteries / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009392:Nephrectomy; D010641:Phenotype; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D018994:Myosin Light Chains; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents; D003900:Desoxycorticosterone; D011189:Potassium Chloride; D009219:Myosin-Light-Chain Kinase