Control of vascular smooth muscle function by Src‐family kinases and reactive oxygen species in health and disease

Charles E. MacKay; Greg A. Knock

doi:10.1113/jphysiol.2014.285304

journal article Dec 01, 2014

Control of vascular smooth muscle function by Src‐family kinases and reactive oxygen species in health and disease

Charles E. MacKay Greg A. Knock

The Journal of Physiology Vol. 593 No. 17 pp. 3815-3828 · Wiley

View at Publisher Save 10.1113/jphysiol.2014.285304

Abstract

AbstractReactive oxygen species (ROS) are now recognised as second messenger molecules that regulate cellular function by reversibly oxidising specific amino acid residues of key target proteins. Amongst these are the Src‐family kinases (SrcFKs), a multi‐functional group of non‐receptor tyrosine kinases highly expressed in vascular smooth muscle (VSM). In this review we examine the evidence supporting a role for ROS‐induced SrcFK activity in normal VSM contractile function and in vascular remodelling in cardiovascular disease. VSM contractile responses to G‐protein‐coupled receptor stimulation, as well as hypoxia in pulmonary artery, are shown to be dependent on both ROS and SrcFK activity. Specific phosphorylation targets are identified amongst those that alter intracellular Ca2+ concentration, including transient receptor potential channels, voltage‐gated Ca2+ channels and various types of K+ channels, as well as amongst those that regulate actin cytoskeleton dynamics and myosin phosphatase activity, including focal adhesion kinase, protein tyrosine kinase‐2, Janus kinase, other focal adhesion‐associated proteins, and Rho guanine nucleotide exchange factors. We also examine a growing weight of evidence in favour of a key role for SrcFKs in multiple pro‐proliferative and anti‐apoptotic signalling pathways relating to oxidative stress and vascular remodelling, with a particular focus on pulmonary hypertension, including growth‐factor receptor transactivation and downstream signalling, hypoxia‐inducible factors, positive feedback between SrcFK and STAT3 signalling and positive feedback between SrcFK and NADPH oxidase dependent ROS production. We also discuss evidence for and against the potential therapeutic targeting of SrcFKs in the treatment of pulmonary hypertension.

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Details

Published: Dec 01, 2014
Vol/Issue: 593(17)
Pages: 3815-3828
License: View

Authors

C

Charles E. MacKay

Asthma, Allergy and Lung Biology, Faculty of Life Sciences and Medicine King's College London London UK

G

Greg A. Knock

Asthma, Allergy and Lung Biology, Faculty of Life Sciences and Medicine King's College London London UK

Cite This Article

Charles E. MacKay, Greg A. Knock (2014). Control of vascular smooth muscle function by Src‐family kinases and reactive oxygen species in health and disease. The Journal of Physiology, 593(17), 3815-3828. https://doi.org/10.1113/jphysiol.2014.285304

Control of vascular smooth muscle function by Src‐family kinases and reactive oxygen species in health and disease

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