KEGG   PATHWAY: ko04270
Entry
ko04270                     Pathway                                

Name
Vascular smooth muscle contraction
Description
The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure.
The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration ([Ca2+]c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase [Ca2+]c in VSMCs. The increase in [Ca2+]c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement.
The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs.
Class
Organismal Systems; Circulatory system
Pathway map
ko04270  Vascular smooth muscle contraction
ko04270

Disease
H00728  Brugada syndrome
H00731  Atrial fibrillation
H00746  Hypokalemic periodic paralysis (HypoPP)
H00801  Familial thoracic aortic aneurysm and dissection
H01258  Generalized epilepsy and paroxysmal dyskinesia
H01396  Moyamoya disease
H01630  Patent ductus arteriosus
Drug
D04789  Lubeluzole (USAN/INN)
Other DBs
GO: 0014829
Orthology
K04135  adrenergic receptor alpha-1A
K04136  adrenergic receptor alpha-1B
K04137  adrenergic receptor alpha-1D
K09821  angiotensinogen
K04166  angiotensin II receptor type 1
K16366  endothelin-1
K16367  endothelin-2
K05227  endothelin-3
K04197  endothelin receptor type A
K05242  arginine vasopressin
K04226  arginine vasopressin receptor 1A
K04227  arginine vasopressin receptor 1B
K04634  guanine nucleotide-binding protein G(q) subunit alpha
K04635  guanine nucleotide-binding protein subunit alpha-11
K01047  secretory phospholipase A2 [EC:3.1.1.4]
K16342  cytosolic phospholipase A2 [EC:3.1.1.4]
K16343  calcium-independent phospholipase A2 [EC:3.1.1.4]
K07425  long-chain fatty acid omega-monooxygenase [EC:1.14.14.80]
K04936  potassium large conductance calcium-activated channel subfamily M alpha member 1
K05274  potassium large conductance calcium-activated channel subfamily M alpha member 3
K04937  potassium large conductance calcium-activated channel subfamily M beta member 1
K04938  potassium large conductance calcium-activated channel subfamily M beta member 2
K04939  potassium large conductance calcium-activated channel subfamily M beta member 3
K04941  potassium large conductance calcium-activated channel subfamily M beta member 4
K04850  voltage-dependent calcium channel L type alpha-1C
K04851  voltage-dependent calcium channel L type alpha-1D
K04853  voltage-dependent calcium channel L type alpha-1F
K04857  voltage-dependent calcium channel L type alpha-1S
K02183  calmodulin
K00907  myosin-light-chain kinase [EC:2.7.11.18]
K12751  myosin light chain 6
K12755  myosin regulatory light chain 9
K10352  myosin heavy chain 9/10/11/14
K05858  phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K04958  inositol 1,4,5-triphosphate receptor type 1
K04959  inositol 1,4,5-triphosphate receptor type 2
K04960  inositol 1,4,5-triphosphate receptor type 3
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K19663  classical protein kinase C gamma type [EC:2.7.11.13]
K06068  novel protein kinase C delta type [EC:2.7.11.13]
K18050  novel protein kinase C epsilon type [EC:2.7.11.13]
K18051  novel protein kinase C eta type [EC:2.7.11.13]
K18052  novel protein kinase C theta type [EC:2.7.11.13]
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K12327  caldesmon
K12313  actin, aortic smooth muscle
K12315  actin, gamma-enteric smooth muscle
K12328  protein phosphatase 1 regulatory subunit 14A
K06269  serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K06270  protein phosphatase 1 regulatory subunit 12A
K12329  protein phosphatase 1 regulatory subunit 12B
K17457  protein phosphatase 1 regulatory subunit 12C
K04346  guanine nucleotide-binding protein subunit alpha-12
K04639  guanine nucleotide-binding protein subunit alpha-13
K07532  Rho guanine nucleotide exchange factor 12
K12330  Rho guanine nucleotide exchange factor 1
K12331  Rho guanine nucleotide exchange factor 11
K04513  Ras homolog gene family, member A
K04514  Rho-associated protein kinase 1 [EC:2.7.11.1]
K17388  Rho-associated protein kinase 2 [EC:2.7.11.1]
K04266  adenosine receptor A2a
K04267  adenosine receptor A2b
K04263  prostacyclin receptor
K12332  calcitonin
K12333  adrenomedullin
K04577  calcitonin receptor-like
K08447  receptor activity modifying protein 1
K08448  receptor activity modifying protein 2
K08449  receptor activity modifying protein 3
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K08041  adenylate cyclase 1 [EC:4.6.1.1]
K08042  adenylate cyclase 2 [EC:4.6.1.1]
K08043  adenylate cyclase 3 [EC:4.6.1.1]
K08044  adenylate cyclase 4 [EC:4.6.1.1]
K08045  adenylate cyclase 5 [EC:4.6.1.1]
K08046  adenylate cyclase 6 [EC:4.6.1.1]
K08047  adenylate cyclase 7 [EC:4.6.1.1]
K08048  adenylate cyclase 8 [EC:4.6.1.1]
K08049  adenylate cyclase 9 [EC:4.6.1.1]
K04345  protein kinase A [EC:2.7.11.11]
K12334  natriuretic peptide A
K12335  natriuretic peptide B
K12323  atrial natriuretic peptide receptor A [EC:4.6.1.2]
K12336  natriuretic peptide C
K12324  atrial natriuretic peptide receptor B [EC:4.6.1.2]
K07376  cGMP-dependent protein kinase 1 [EC:2.7.11.12]
K12337  inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate
K12318  guanylate cyclase soluble subunit alpha [EC:4.6.1.2]
K12319  guanylate cyclase soluble subunit beta [EC:4.6.1.2]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00212  Adenosine
C00219  Arachidonate
C00238  Potassium cation
C00533  Nitric oxide
C00547  L-Noradrenaline
C00575  3',5'-Cyclic AMP
C00942  3',5'-Cyclic GMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01312  Prostaglandin I2
C14748  20-HETE
C14768  5,6-EET
C14769  8,9-EET
C14770  11,12-EET
C14771  14,15-EET
Reference
  Authors
Akata T
  Title
Cellular and molecular mechanisms regulating vascular tone. Part 2: regulatory mechanisms modulating Ca2+ mobilization and/or myofilament Ca2+ sensitivity in vascular smooth muscle cells.
  Journal
J Anesth 21:232-42 (2007)
DOI:10.1007/s00540-006-0488-4
Reference
  Authors
Ogut O, Brozovich FV
  Title
Regulation of force in vascular smooth muscle.
  Journal
J Mol Cell Cardiol 35:347-55 (2003)
DOI:10.1016/S0022-2828(03)00045-2
Reference
  Authors
Hilgers RH, Webb RC
  Title
Molecular aspects of arterial smooth muscle contraction: focus on Rho.
  Journal
Exp Biol Med (Maywood) 230:829-35 (2005)
DOI:10.1177/153537020523001107
Reference
  Authors
Schlossmann J, Feil R, Hofmann F
  Title
Signaling through NO and cGMP-dependent protein kinases.
  Journal
Ann Med 35:21-7 (2003)
DOI:10.1080/07853890310004093
Reference
  Authors
Mehta PK, Griendling KK
  Title
Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.
  Journal
Am J Physiol Cell Physiol 292:C82-97 (2007)
DOI:10.1152/ajpcell.00287.2006
Reference
  Authors
Kim HR, Appel S, Vetterkind S, Gangopadhyay SS, Morgan KG
  Title
Smooth muscle signalling pathways in health and disease.
  Journal
J Cell Mol Med 12:2165-80 (2008)
DOI:10.1111/j.1582-4934.2008.00552.x
Reference
  Authors
Fukata Y, Amano M, Kaibuchi K
  Title
Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells.
  Journal
Trends Pharmacol Sci 22:32-9 (2001)
DOI:10.1016/S0165-6147(00)01596-0
Reference
  Authors
Dimopoulos GJ, Semba S, Kitazawa K, Eto M, Kitazawa T
  Title
Ca2+-dependent rapid Ca2+ sensitization of contraction in arterial smooth muscle.
  Journal
Circ Res 100:121-9 (2007)
DOI:10.1161/01.RES.0000253902.90489.df
Reference
  Authors
Hynynen MM, Khalil RA
  Title
The vascular endothelin system in hypertension--recent patents and discoveries.
  Journal
Recent Pat Cardiovasc Drug Discov 1:95-108 (2006)
DOI:10.2174/157489006775244263
Reference
  Authors
Brain SD, Grant AD
  Title
Vascular actions of calcitonin gene-related peptide and adrenomedullin.
  Journal
Physiol Rev 84:903-34 (2004)
DOI:10.1152/physrev.00037.2003
Reference
  Authors
Roman RJ
  Title
P-450 metabolites of arachidonic acid in the control of cardiovascular function.
  Journal
Physiol Rev 82:131-85 (2002)
DOI:10.1152/physrev.00021.2001
Reference
  Authors
Surks HK
  Title
cGMP-dependent protein kinase I and smooth muscle relaxation: a tale of two isoforms.
  Journal
Circ Res 101:1078-80 (2007)
DOI:10.1161/CIRCRESAHA.107.165779
Reference
  Authors
Vanhoutte PM
  Title
Endothelium-dependent hyperpolarizations: the history.
  Journal
Pharmacol Res 49:503-8 (2004)
DOI:10.1016/j.phrs.2003.11.015
Reference
  Authors
Davis MJ, Hill MA
  Title
Signaling mechanisms underlying the vascular myogenic response.
  Journal
Physiol Rev 79:387-423 (1999)
DOI:10.1152/physrev.1999.79.2.387
Reference
  Authors
Fleming I.
  Title
Cytochrome p450 and vascular homeostasis.
  Journal
Circ Res 89:753-62 (2001)
DOI:10.1161/hh2101.099268
Reference
  Authors
Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP
  Title
Molecular mechanism of cGMP-mediated smooth muscle relaxation.
  Journal
Reference
  Authors
Ko EA, Han J, Jung ID, Park WS
  Title
Physiological roles of K+ channels in vascular smooth muscle cells.
  Journal
J Smooth Muscle Res 44:65-81 (2008)
DOI:10.1540/jsmr.44.65
Reference
  Authors
Woodard GE, Rosado JA
  Title
Natriuretic peptides in vascular physiology and pathology.
  Journal
Int Rev Cell Mol Biol 268:59-93 (2008)
DOI:10.1016/S1937-6448(08)00803-4
Reference
  Authors
Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG
  Title
Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide.
  Journal
Am J Physiol Heart Circ Physiol 281:H2337-65 (2001)
DOI:10.1152/ajpheart.2001.281.6.H2337
Reference
  Authors
Hirano K, Hirano M, Kanaide H
  Title
Regulation of myosin phosphorylation and myofilament Ca2+ sensitivity in vascular smooth muscle.
  Journal
J Smooth Muscle Res 40:219-36 (2004)
DOI:10.1540/jsmr.40.219
Reference
PMID:9458738
  Authors
Freeman EJ, Ruehr ML, Dorman RV
  Title
ANG II-induced translocation of cytosolic PLA2 to the nucleus in vascular smooth muscle cells.
  Journal
Am J Physiol 274:C282-8 (1998)
DOI:10.1152/ajpcell.1998.274.1.C282
Reference
  Authors
Murphy TV, Spurrell BE, Hill MA
  Title
Cellular signalling in arteriolar myogenic constriction: involvement of tyrosine phosphorylation pathways.
  Journal
Clin Exp Pharmacol Physiol 29:612-9 (2002)
DOI:10.1046/j.1440-1681.2002.03698.x
Related
pathway
ko00590  Arachidonic acid metabolism
ko04020  Calcium signaling pathway

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