Impaired vascular contractility and blood pressure homeostasis in the smooth muscle α‐actin null mouse

Abstract

The smooth muscle (SM) alpha-actin gene activated during the early stages of embryonic cardiovascular development is switched off in late stage heart tissue and replaced by cardiac and skeletal alpha-actins. SM alpha-actin also appears during vascular development, but becomes the single most abundant protein in adult vascular smooth muscle cells. Tissue-specific expression of SM alpha-actin is thought to be required for the principal force-generating capacity of the vascular smooth muscle cell. We wanted to determine whether SM alpha-actin gene expression actually relates to an actin isoform's function. Analysis of SM alpha-actin null mice indicated that SM alpha-actin is not required for the formation of the cardiovascular system. Also, SM alpha-actin null mice appeared to have no difficulty feeding or reproducing. Survival in the absence of SM alpha-actin may result from other actin isoforms partially substituting for this isoform. In fact, skeletal alpha-actin gene, an actin isoform not usually expressed in vascular smooth muscle, was activated in the aortas of these SM alpha-actin null mice. However, even with a modest increase in skeletal alpha-actin activity, highly compromised vascular contractility, tone, and blood flow were detected in SM alpha-actin-defective mice. This study supports the concept that SM alpha-actin has a central role in regulating vascular contractility and blood pressure homeostasis, but is not required for the formation of the cardiovascular system.

Smooth Muscle Actin Determines Mechanical Force-induced p38 Activation

“…p38 Activation and SMA-Analysis of SMA null mice has established a central role for this actin isoform in regulating vascular contractility and blood pressure homeostasis (48), but prior to the present report, the functional importance of SMA in mediating force-induced activation of p38 has not been demonstrated. We used RNAi (49) to selectively knockdown SMA and thereby determine its functional role in force-induced p38 activation.…”

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

“…Inactivation of SmoothelinA, encoding a visceral smooth muscle restricted actin-binding protein (42), results in impaired intestinal contractility and 50% mortality in homozygous mutants by postnatal day 20 (43); no human mutations have yet been reported for SmoothelinA. Surprisingly, mice in which the smooth muscle alpha actin gene (Acta2) is inactivated survive with mild hypotension and reduced blood flow under thermal challenge; no gastrointestinal or urinary pathologies were reported (44). Compensatory increases in the skeletal alpha actin isoform (ACTA1), as well as the dominant expression of the gamma isoform of smooth muscle actin (ACTG2) in visceral smooth muscle (45), likely compensate for loss of ACTA2 in the gastrointestinal and urinary tracts.…”

Cell biology of embryonic migration

“…Mouse knockouts of cell migration components or other proteins with direct effects on cell migration Protein Function Type Phenotype Reference α skeletal muscle actin Actin Cytoskeleton Total Postnatal death at P1-9, marked loss of body weight; upregulation of other actin isoforms (Crawford et al, 2002) α smooth muscle actin Actin Cytoskeleton Total Viable; impaired vascular contractility and blood pressure homeostasis; upregulation of other actin isoforms (Schildmeyer et al, 2000) α cardiac actin Actin Cytoskeleton Total Perinathal lethality; cardiac hypertrophy and heart muscle abnormalities; upregulation of other actin isoforms (Kumar et al, 1997) β non-muscle actin Actin Cytoskeleton Total Death after E9.5 (Shawlot et al, 1998) γ non-muscle actin Actin Cytoskeleton Skeletal muscle-specific Muscle weakness, necrosis and degeneration (Sonnemann et al, 2006) Tropomyosin Actin Cytoskeleton Total Death before morula stage (Hook et al, 2004) Mena Actin Cytoskeleton Total Viable, with misrouted axons and defects in the nervous system (Lanier et al, 1999) Mena, VASP, Evl triple null Actin Cytoskeleton Total Defects in brain development, neuritogenesis, and neural tube closure Filamin-B Actin Cytoskeleton Total Skeletal malformations and impaired microvascular development (Zhou et al, 2007) Gelsolin (or ADF) Actin Cytoskeleton Total Defects in fibroblast and platelet motility and lamellar responses (Witke et al, 1995) Nonmuscle myosin II-B Actin Cytoskeleton Total Embryonic and perinatal lethality with severe heart defects (Tullio et al, 1997) Myosin heavy chain II-A Actin Cytoskeleton Total Failure in embryonic patterning, embryonic lethality by E7.5 (Conti et al, 2004) Cardiac alpha myosin, heavy chain Actin Cytoskeleton Total Embryonic lethality between E11 and 12 with gross heart defects (Jones, 1996) (Imamoto and Soriano, 1993;Nada et al, 1993) Ephrin B1 Transmembrane signaling Total Neural crest cell misguidance (cranial and cardiac, but not trunk) (Davy et al, 2004) Angiomotin Transmembrane signaling Total Death between E11-E11.5, severe vascular insufficiency in intersomitic regions, dilated vessels in the brain (Aase et al, 2007) Birth Defects Res C Embryo Today. Author manuscript; available in PMC 2009 June 1.…”