Smooth Muscle and Extracellular Matrix Interactions in Health and Disease

Alterations in smooth muscle cell function and phenotype contribute to tissue remodeling in various pathologies including obstructive lung (e.g., asthma) and vascular (e.g., atherosclerosis) diseases. The extracellular matrix (ECM) is a major influence on the biology of smooth muscle cells, being an important support structure that provides signaling cues through its biochemical and biophysical properties. ECM factors activate biochemical and mechano-transduction signaling pathways, which modulate smooth muscle cell contraction, stiffness, survival, growth, cytokine production and migration (i.e., cellular processes which contribute to changes in tissue architecture). The interaction of the ECM with smooth muscle cells is a dynamic multi-directional process, as smooth muscle cells also produce ECM protein, as well as proteases and cross-linking enzymes which regulate ECM form and structure. Understanding the molecular basis of ECM modifications and their impact on smooth muscle cell function in disease may lead to the development of novel therapies. This chapter reviews interactions between the ECM and smooth muscle cell and how they become altered in disease, using obstructive lung and vascular diseases as examples. From a pharmacological and therapeutic perspective, strategies that alter the phenotype of the smooth muscle cell in disease will be discussed. Emphasis will be given to approaches that target the proteases and mediators of ECM-smooth muscle cell signaling as potential treatments for pulmonary and vascular disease. Proteases of the coagulation and plasminogen activation systems have been given particular attention as they not only have a role in forming and modifying ECM, but also can directly stimulate changes in smooth muscle cell function and phenotype via activating receptors such as the protease-activated receptor-1 (PAR-1) and integrins