Understanding the role of the extracellular matrix in cardiovascular development and disease: Where do we go from here?

For many years, analyses of the heart have focused primarily on the role of the myocytes as the principal cell type that generates force. Analyses of the extracellular matrix (ECM) were deemed important, but primarily relevant only in hypertrophy and after myocardial infarction. Related to the ECM was the role of the fibroblast, the principal cell type that makes the ECM. When analyses of the ECM were performed, the focus was primarily on interstitial collagen. This reductionist approach was also incorporated into the experimental design of in vitro studies that used planar two-dimensional culture systems. Even though studies to show that the ECM was a three-dimensional network were first presented in the early 1900’s,[1] it was not until dramatic scanning electron micrographs in the 1980’s showed the three-dimensional structure that we began to appreciate how ECM structure can directly regulate cardiac function. In these studies, however, only myocytes were observed in relation to the collagen network.[2] Most papers cited the studies of Zak and colleagues showing that the number of myocyte was 30% and the non-myocyte population was 70% based on anti-myosin staining and electron microscopy.[3, 4] These basic numbers of myocytes and other cell types remained dogma until recently, when Banerjee and colleagues showed that the number of fibroblasts varied dramatically by species, stage of development, and physiological condition.[5] In addition, we now know that fibroblasts form a three-dimensional network within the collagen network to form intimate cell-cell contacts with myocytes, other fibroblasts, and endothelial cells. At the present time, we know that the heart is a dynamic organ, and physiological function is the result of multiple cellular and acellular components. It is the dynamic interaction of chemical, mechanical and electrical factors generated by the cellular components, together with ECM components, that determine the physiological performance of the heart at various stages of development and in response to pathophysiological signals. Analysis of one component in isolation provides only a partial picture of function. Similar trends have evolved with in vitro studies, where planar two-dimensional techniques provide a distorted view of various cardiac cell type functions and cells plated on a collagen-only matrix do not allow the function and interactions of other ECM components to be evaluated. Three-dimensional culture techniques using ECM that more completely recapitulates in vivo phenotypes will allow us to interrogate the complexity of individual cells, heterotypic cell interactions, and the dynamics of cellular interactions with the ECM. In this special issue, we have assembled a series of reviews that summarizes past investigations but, more importantly, raises new questions as to the role of the ECM in cardiac function. We have chosen topics and investigators who address these concepts. The major themes of this issue are: 1) ECM in specific diseases and with specific cell interactions; 2) particular ECM components; 3) engineering issues related to ECM; 4) diagnostic potential of altered ECM; and 5) how ECM in other tissues compare and contrast with cardiac ECM. We asked each author to limit his/her review to 5000 words and 50 references, to allow the maximum number of articles and provide the largest topic coverage. The reviews in this issue focus on the ECM in normal development as well as in response to specific diseases, including hypertension, myocardial infarction, and atrial fibrillation. The following review articles demonstrate the complexity of the interactions between both cellular and acellular components, with emphasis given to the role of the environment on cell function. In addition, future directions are discussed in depth to provide information on the key experiments that need to be performed for us to gain a more complete understanding of ECM roles. Critical to ECM remodeling is the dynamic interactions between the ECM and the matrix metalloproteinases (MMPs) that break down ECM components; the relationship between MMPs and the endogenous tissue inhibitors of metalloproteinases (TIMPs); and the connection between cytokines and both ECM components and MMPs. The range of topics covered include the dynamics of ECM changes in volume overload (Lucchesi)[6], and ECM regulation by the renin-angiotensin-aldosterone system (Sun)[7] and the inflammation system during myocardial infarction (Frangogiannis)[8], viral myocarditis (Westermann) [9], pulmonary disease (Lagente)[10], and cardiac development (Baudino)[11]. Atrial fibrillation is highly associated with fibrosis, and the role of ECM during atrial remodeling is reviewed here (Sheikh)[12]. The challenges of using ultrasound to monitor the progression of remodeling (Scherrer-Crosbie)[13] and applying diagnostic approaches to evaluate fibrosis in the setting of diabetes (Villarreal)[14] are also covered. Targeting particular individual ECM components yields specific responses to stress and injury, and we have included discussions on the functions of non-fibrillar collagens (Meszaros)[15], osteopontin (Singh)[16], secreted protein acidic and rich in cysteine (Bradshaw)[17], the matrix metalloproteinases (Lindsey)[18] and the tissue inhibitors of metalloproteinases (Vanhoutte)[19] in this issue. How the response to injury in other organs may predict cardiac function is covered by unique evaluations of how changes in the skin (Gourdie)[20] and kidney (Kalluri)[21] can inform us about cardiac changes. The idea that the reaction of skin to injury could be used to predict outcome following myocardial infarction or hypertension both alone or in the setting of diabetes is one example of how comparative studies of extracellular matrix among the organs is warranted. A unique aspect of the ECM in the heart is the presence of continuous cyclic and static mechanical tension. While ECM is altered by changes in mechanical properties and ECM is often evaluated as an end point measurement, ECM changes also initiate many downstream signaling cascades by altering mechanical conditions in a positive feedback manner (Holmes)[22] and by generating ECM peptides to serve as signaling molecules (Davis)[23]. Many of the articles presented focus on cardiac effects of ECM, but the ECM is also crucial to the normal growth and response to pathological and repair signals in the vasculature (Lehoux)[24]. Central to this theme is the role of edema and fluid dynamics, which is also discussed here (Reed)[25]. In summary, these reviews comprehensively evaluate the current state of understanding of ECM roles in cardiovascular development and disease. More importantly, the set of articles presented in this special issue underscores the challenges that remain before we can more completely understand the dynamics of cardiovascular cellular and extracellular interactions. Areas and common themes that remain fruitful for future research are highlighted in Table 1. Together, this special issue highlights the current themes of cardiovascular ECM and points us in the directions where future research can be focused. Table 1 Key Future Directions for Cardiovascular Extracellular Matrix Research