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

Drug
D04789  Lubeluzole (USAN/INN)
Other DBs
GO: 0014829
Orthology
K00907  MYLK; myosin-light-chain kinase [EC:2.7.11.18]
K01047  PLA2G, SPLA2; secretory phospholipase A2 [EC:3.1.1.4]
K02183  CALM; calmodulin
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K04135  ADRA1A; adrenergic receptor alpha-1A
K04136  ADRA1B; adrenergic receptor alpha-1B
K04137  ADRA1D; adrenergic receptor alpha-1D
K04166  AGTR1; angiotensin II receptor type 1
K04197  EDNRA; endothelin receptor type A
K04226  AVPR1A; arginine vasopressin receptor 1A
K04227  AVPR1B; arginine vasopressin receptor 1B
K04263  PTGIR; prostacyclin receptor
K04266  ADORA2A, ADOR; adenosine receptor A2a
K04267  ADORA2B; adenosine receptor A2b
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04346  GNA12; guanine nucleotide-binding protein subunit alpha-12
K04365  BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04513  RHOA; Ras homolog gene family, member A
K04514  ROCK1; Rho-associated protein kinase 1 [EC:2.7.11.39]
K04577  CALCRL; calcitonin receptor-like
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04635  GNA11; guanine nucleotide-binding protein subunit alpha-11
K04639  GNA13; guanine nucleotide-binding protein subunit alpha-13
K04850  CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C
K04851  CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D
K04853  CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F
K04857  CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S
K04936  KCNMA1, KCA1.1; potassium large conductance calcium-activated channel subfamily M alpha member 1
K04937  KCNMB1; potassium large conductance calcium-activated channel subfamily M beta member 1
K04938  KCNMB2; potassium large conductance calcium-activated channel subfamily M beta member 2
K04939  KCNMB3; potassium large conductance calcium-activated channel subfamily M beta member 3
K04941  KCNMB4; potassium large conductance calcium-activated channel subfamily M beta member 4
K04958  ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959  ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960  ITPR3; inositol 1,4,5-triphosphate receptor type 3
K05227  EDN3; endothelin-3
K05242  AVP; arginine vasopressin
K05274  KCNMA3, KCNU1, KCA5.1; potassium large conductance calcium-activated channel subfamily M alpha member 3
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K06068  PRKCD; novel protein kinase C delta type [EC:2.7.11.13]
K06269  PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K06270  PPP1R12A, MYPT1; protein phosphatase 1 regulatory subunit 12A
K07376  PRKG1; cGMP-dependent protein kinase 1 [EC:2.7.11.12]
K07425  CYP4A; long-chain fatty acid omega-monooxygenase [EC:1.14.14.80]
K07532  ARHGEF12, LARG; Rho guanine nucleotide exchange factor 12
K08041  ADCY1; adenylate cyclase 1 [EC:4.6.1.1]
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08043  ADCY3; adenylate cyclase 3 [EC:4.6.1.1]
K08044  ADCY4; adenylate cyclase 4 [EC:4.6.1.1]
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08046  ADCY6; adenylate cyclase 6 [EC:4.6.1.1]
K08047  ADCY7; adenylate cyclase 7 [EC:4.6.1.1]
K08048  ADCY8; adenylate cyclase 8 [EC:4.6.1.1]
K08049  ADCY9; adenylate cyclase 9 [EC:4.6.1.1]
K08447  RAMP1; receptor activity modifying protein 1
K08448  RAMP2; receptor activity modifying protein 2
K08449  RAMP3; receptor activity modifying protein 3
K08845  ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K09821  AGT, SERPINA8; angiotensinogen
K10352  MYH9s; myosin heavy chain 9/10/11/14
K12313  ACTA2; actin, aortic smooth muscle
K12315  ACTG2; actin, gamma-enteric smooth muscle
K12318  GUCY1A; guanylate cyclase soluble subunit alpha [EC:4.6.1.2]
K12319  GUCY1B; guanylate cyclase soluble subunit beta [EC:4.6.1.2]
K12323  ANPRA, NPR1; atrial natriuretic peptide receptor A [EC:4.6.1.2]
K12324  ANPRB, NPR2; atrial natriuretic peptide receptor B [EC:4.6.1.2]
K12327  CALD1; caldesmon
K12328  PPP1R14A, CPI17; protein phosphatase 1 regulatory subunit 14A
K12329  PPP1R12B, MYPT2; protein phosphatase 1 regulatory subunit 12B
K12330  ARHGEF1; Rho guanine nucleotide exchange factor 1
K12331  ARHGEF11; Rho guanine nucleotide exchange factor 11
K12332  CALC; calcitonin
K12333  ADM; adrenomedullin
K12334  NPPA; natriuretic peptide A
K12335  NPPB; natriuretic peptide B
K12336  NPPC; natriuretic peptide C
K12337  MRVI1, IRAG; inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate
K12751  MYL6; myosin light chain 6
K12755  MYL9; myosin regulatory light chain 9
K16342  PLA2G4, CPLA2; cytosolic phospholipase A2 [EC:3.1.1.4]
K16343  PLA2G6, IPLA2; calcium-independent phospholipase A2 [EC:3.1.1.4]
K16366  EDN1; endothelin-1
K16367  EDN2; endothelin-2
K17388  ROCK2; Rho-associated protein kinase 2 [EC:2.7.11.39]
K17457  PPP1R12C, MBS85; protein phosphatase 1 regulatory subunit 12C
K18050  PRKCE; novel protein kinase C epsilon type [EC:2.7.11.13]
K18051  PRKCH; novel protein kinase C eta type [EC:2.7.11.13]
K18052  PRKCQ; novel protein kinase C theta type [EC:2.7.11.13]
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
K25343  ADM2; adrenomedullin-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
PMID:17458653
  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
PMID:12689814
  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
PMID:16339747
  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
PMID:12693609
  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
PMID:16870827
  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
PMID:19120701
  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
PMID:11165670
  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
PMID:17158339
  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
PMID:17200683
  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
PMID:15269340
  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
PMID:11773611
  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
PMID:18040024
  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
PMID:15026027
  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
PMID:10221985
  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
PMID:11679404
  Authors
Fleming I.
  Title
Cytochrome p450 and vascular homeostasis.
  Journal
Circ Res 89:753-62 (2001)
DOI:10.1161/hh2101.099268
Reference
PMID:10911373
  Authors
Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP
  Title
Molecular mechanism of cGMP-mediated smooth muscle relaxation.
  Journal
J Cell Physiol 184:409-20 (2000)
DOI:10.1002/1097-4652(200009)184:3<409::AID-JCP16>3.0.CO;2-K
Reference
PMID:18552454
  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
PMID:18703404
  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
PMID:11709400
  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
PMID:15725705
  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
PMID:12060106
  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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