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Novel signal transduction targets in cardiovascular disease: Role of platelet‐derived growth factor in vascular smooth muscle cell proliferation
Author(s) -
Molloy Christopher J.
Publication year - 1993
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430290210
Subject(s) - platelet derived growth factor receptor , vascular smooth muscle , platelet derived growth factor , growth factor , microbiology and biotechnology , signal transduction , receptor , biology , cancer research , endocrinology , medicine , biochemistry , smooth muscle
Proliferation and directed migration of vascular smooth muscle cells (VSMCs) are important components in such processes as hypertension‐induced vascular remodeling, vascular restenosis, and atherosclerosis. However, the cellular mechanisms involved in the control of VSMC growth and migration at the tissue level remain largely undefined. Platelet‐derived growth factor (PDGF) has been identified as one of the most potent endogenous VSMC mitogens/chemoattractants. PDGF consists of disulfide‐linked polypeptide dimers composed of two distinct gene products, designated A‐chain and B‐chain. These are assembled as either heterodimers (e.g., AB) or homodimers (e.g., AA, BB). Two distinct PDGF‐receptor genes have been identified, designated α and β. Elevated vascular expression of PDGF‐A and ‐B chains and PDGF‐receptors has been observed in cardiovascular disorders and their related animal models, including restenosis and atherosclerosis. For example, in the rat ballon‐injury model, infusion of PDGF greatly increases intimal thickening and migration of VSMC [Jawien et al. (1992): J Clin Invest 89:507–511]. Furthermore, in a similar model, PDGF‐neutralizing antibodies significantly reduce intimal thickening following balloon injury [Ferns et al. (1991): Science 253:1129–1132]. Thus, PDGF may have a pivotal role in the pathophysiology of hyperproliferative vascular diseases. Pharmacological antagonism of PDGF can be directed at distinct cellular sites, related to the biochemical signaling pathways involved in PDGF‐initiated signal transduction. These include inhibition of ligand binding to high‐affinity surface receptors, inhibition of activated PDGF‐receptor tyrosine kinases, interruption of intracellular PDGF‐receptor‐protein interactions, and inhibition of secondary signaling enzymes. Future development of specific PDGF antagonists will allow precise elucidation of the role of this potent growth factor in cardiovascular diseases. © 1993 Wiley‐Liss, Inc.