Abstract
Our understanding of the molecular events contributing to myogenic control of diameter in cerebral resistance arteries in response to changes in intravascular pressure, a fundamental mechanism regulating blood flow to the brain, is incomplete. Myosin light chain kinase and phosphatase activities are known to be increased and decreased, respectively, to augment phosphorylation of the 20-kDa regulatory light chain subunits (LC20) of myosin II, which permits cross-bridge cycling and force development. Here, we assessed the contribution of dynamic reorganization of the actin cytoskeleton and thin filament regulation to the myogenic response and serotonin-evoked constriction of pressurized rat middle cerebral arteries. Arterial diameter and the levels of phosphorylated LC(20), calponin, caldesmon, cofilin, and HSP27, as well as G-actin content, were determined. A decline in G-actin content was observed following pressurization from 10 mm Hg to between 40 and 120 mm Hg and in three conditions in which myogenic or agonist-evoked constriction occurred in the absence of a detectable change in LC20 phosphorylation. No changes in thin filament protein phosphorylation were evident. Pressurization reduced G-actin content and elevated the levels of cofilin and HSP27 phosphorylation. Inhibitors of Rho-associated kinase and PKC prevented the decline in G-actin; reduced cofilin and HSP27 phosphoprotein content, respectively; and blocked the myogenic response. Furthermore, phosphorylation modulators of HSP27 and cofilin induced significant changes in arterial diameter and G-actin content of myogenically active arteries. Taken together, our findings suggest that dynamic reorganization of the cytoskeleton involving increased actin polymerization in response to Rho-associated kinase and PKC signaling contributes significantly to force generation in myogenic constriction of cerebral resistance arteries.
Highlights
The myogenic response of cerebral arteries to intravascular pressure regulates blood flow to the brain
Decreased G-actin Content Associated with Myogenic- or Agonist-evoked Constriction in the Absence of Alterations in LC20, Calponin, or Caldesmon Phosphorylation—Rat middle cerebral arteries (RMCAs) constriction under conditions in which a detectable change in the level of LC20 phosphorylation was not apparent was examined to assess the contribution of thin filament regulatory phosphoproteins and cytoskeletal reorganization to force development
This study examined the role of thin filament regulatory proteins, calponin and caldesmon, and dynamic reorganization of the actin cytoskeleton in the myogenic response and agonistevoked constriction of pressurized rat cerebral arteries
Summary
The myogenic response of cerebral arteries to intravascular pressure regulates blood flow to the brain. Dynamic reorganization of the actin cytoskeleton during smooth muscle contraction is thought to involve expansion of adhesion protein complexes, severing of existing filaments to provide nucleation sites, and de novo actin polymerization of globular to filamentous actin (G- and F-actin, respectively) within the cortical actin network beneath the cell membrane [25, 39] This is postulated to strengthen the cytoskeleton and enhance force transmission from the contractile apparatus to the cell membrane and extracellular matrix [24, 25]. Force generation caused by actin polymerization was detected independent of a change in LC20 phosphorylation and crossbridge cycling in the myogenic response and in vasoconstrictor-evoked contraction of myogenic arteries, accounting for ϳ30% of myogenic tone at 120 mm Hg. Evidence supporting a role for two regulators of actin dynamics, cofilin and HSP27, that are known to be regulated by ROK and PKC, respectively, was obtained
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