Michael Schuliga

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60403

#### **Abstract**

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 multidirectional 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.

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Keywords:** Extracellular matrix (ECM), Coagulation, Collagen, Fibrinolysis, Integ‐ rins, Proteases

### **1. Introduction**

Smooth muscle cells function by contracting following activation of actin and myosin fila‐ ments, in a process involving myosin light chain phosphorylation, mediated by Ca2+-depend‐ ent pathways [1]. In many diseases, alterations in smooth muscle cell function including contractile responses, growth and phenotype, contribute to tissue remodeling. In obstructive lung diseases such as severe asthma and chronic obstructive pulmonary disease (COPD), increases in the stiffness and mass of the airway smooth muscle (ASM) bundle contribute to fixed airway obstruction and hyper-responsiveness [2, 3]. In vascular injury and diseases such as atherosclerosis and pulmonary arterial hypertension (PAH), the migration, stiffening, proliferation and growth of vascular smooth muscle (VSM) cells contribute to the enlargement of the blood vessel wall, which in effect reduces lumen size, thus an increase in vascular resistance [4, 5]. Alterations in the microenvironment of the smooth muscle cell, particularly in the composition and structure of the ECM, accompany changes in smooth muscle biology in disease. Smooth muscle cells have a large role in modifying their microenvironment in disease by producing ECM protein (*e.g.,* collagen, fibrin, fibronectin and proteoglycans [6]) and factors which regulate ECM formation (*e.g.,* tissue factor in fibrin formation [7]). Further‐ more, smooth muscle cells secrete proteases (*e.g.,* urokinase plasminogen activator or uPA [8]) and crosslinking enzymes (*e.g.,* lysyl oxidases [9]) which modulate ECM structure and form. The ECM in turn regulates smooth muscle function by the provision of both biochemical and biomechanical cues, in a process involving complexes formed between integrins, focal adhesion (FA) proteins and the actin-cytoskeleton. Both biochemical and mechano-transduc‐ tion signaling in smooth muscle cells are mutually interdependent. In disease, the altered ECM may perpetuate tissue remodeling by augmenting smooth muscle growth, migration, cytokine production, cell stiffness and proliferation in a detrimental feed forward mechanism. Aside from important biomechanical contributions in tissue remodelling, smooth muscle cells are also potent producers of an array of inflammatory mediators, including cytokines, chemokines and cell adhesion molecules (CAMs) [10-13]. These inflammatory mediators, as well as the ECM produced by smooth muscle cells, influence the type and quantity of inflammatory cells that infiltrate damaged tissue in disease [14, 15].

### **2. Smooth muscle cells**

Smooth muscle cells are phenotypically-plastic stromal cells, which are very capable of differentiating in response to injury and inflammation in disease. Whilst myogenic, the structure, mechanical properties, contractility and function of smooth muscle cells are different to those of striated and cardiac muscle cells. The involuntary non-striated smooth muscle cells are found in many tissues and organs including the gastro-intestinal tract, the respiratory system, reproductive tract, urinary bladder, skin, iris of the eyes, kidneys and blood vessels. Smooth muscle cells contract and relax to regulate the luminal diameter and viscoelasticity of conducting vessels (*e.g.*, the vasculature and bronchioles) [16] and sphincters (*e.g.,* the urethral and pre-capillary sphincters) [17]. Smooth muscle contraction also has a role in the rhythmic peristalsis of tissues and organs of the gastro-intestinal tract and respiratory systems [18]. Whilst the structure and function of smooth muscle cells in different tissues are quite similar, they can contrast in their mode of activation, whether that be spontaneous involving ionic channel dynamics or by physiochemical agents (*e.g.*, hormones and neurotransmitters) or external agents (*e.g.*, CO2). The actin-myosin contractile apparatus mediates the force genera‐ tion responsible for smooth muscle contraction, whether that contraction is phasic or tonic (*i.e.,* rapid versus sustained contraction) [19]. Contraction is initiated by calcium-regulated myosin light chain phosphorylation, involving calmodulin rather than the calcium-activated troponin system (as in striated and cardiac muscle), and involves the sliding of actin-myosin filaments [1].
