Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells
- Medical Research Council of Canada Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada
Abstract
Until recently, the signaling events elicited in vascular smooth muscle cells by angiotensin II (Ang II) were considered to be rapid, short-lived, and divided into separate linear pathways, where intracellular targets of the phospholipase C-diacylglycerol-Ca2+ axis were distinct from those of the tyrosine kinase- and mitogen-activated protein kinase- dependent pathways. However, these major intracellular signaling cascades do not function independently and are actively engaged in cross-talk. Downstream signals from the Ang II-bound receptors converge to elicit complex and multiple responses. The exact adapter proteins or “go-between” molecules that link the multiple intracellular pathways await clarification. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of angiotensin receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways in vascular smooth cells may be pivotal in structural and functional abnormalities that underlie vascular pathological processes in cardiovascular diseases such as hypertension, atherosclerosis, and post-interventional restenosis.
Footnotes
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↵1 Address for correspondence: R. M. Touyz, M.D., Ph.D., Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Quebec H2W 1R7 Canada. E-mail: touyzr{at}ircm.qc.ca
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c-Jun N-terminal kinase; PKB, protein kinase B; SAPK, stress-activated protein kinase; MKP, MAP kinase phosphatase; PHAS-I, phosphorylated heat- and acid-stable protein; eIF, eukaryotic initiation factor; PKA, protein kinase A; PG, prostaglandin; TXA, thromboxane; HPETE, hydroperoxyeicosatetraenoic acid; HETE, hydroxyeicosatetraenoic acid; CRE, cAMP/calcium response element; SRE, seum response element; SIE, sis-inducing factor element ; TGF-β, transforming growth factor-β; IGF-1, insulin-like growth factor-1; bFGF, basic fibroblast growth factor; PAF, platelet-activating factor; TNF-α, tumor necrosis factor-α; MCP-1, monocyte chemoattractant protein-1; SHR, spontaneously hypertensive rats; WKY, Wistar-Kyoto; MEK, MAPK/ERK kinase.
- Abbreviations:
- Ang
- angiotensin
- ET-1
- endothelin-1
- PDGF
- platelet-derived growth factor
- RAS
- renin-angiotensin system
- ACE
- angiotensin-converting enzyme
- NEP
- neutral endopeptidase
- GRK
- G protein receptor kinase
- SH2
- Src homology 2
- EGF
- epidermal growth factor
- FAK
- focal adhesion kinase
- PLC
- phospholipase C
- PLA2
- phospholipase A2
- PLD
- phospholipase D
- MAPK
- mitogen-activated protein kinase
- PKC
- protein kinase C
- DAG
- diacylglycerol
- PtdInsP2
- phosphatidylinositol-4,5-bisphosphate
- PYK
- proline-rich tyrosine kinase
- PKD
- protein kinase D
- ERK
- extracellular signal-regulated kinase
- STAT
- signal transducers and activators of transcription
- PI3K
- phosphatidylinositol 3-kinase
- CADTK
- calcium-dependent tyrosine kinase
- The American Society for Pharmacology and Experimental Therapeutics
