The Non-Fibrillar Side of Fibrosis: Contribution of the Basement Membrane, Proteoglycans, and Glycoproteins to Myocardial Fibrosis

The extracellular matrix (ECM) provides structural support and a microenvironmentfor soluble extracellular molecules. ECM is comprised of numerous proteins which can be broadly classified as fibrillar (collagen types I and III) and non-fibrillar (basement membrane, proteoglycans, and glycoproteins). The basement membrane provides an interface between the cardiomyocytes and the fibrillar ECM, while proteoglycans sequester soluble growth factors and cytokines. Myocardial fibrosis was originally only linked to accumulation of fibrillar collagens, but is now recognized as the expansion of the ECM including the non-fibrillar ECM proteins. Myocardial fibrosis can be reparative to replace the lost myocardium (e.g., ischemic injury or myocardial infarction), or can be reactive resulting from pathological activity of fibroblasts (e.g., dilated or hypertrophic cardiomyopathy). Contribution of fibrillar collagens to fibrosis is well studied, but the role of the non-fibrillar ECM proteins has remained less explored. In this article, we provide an overview of the contribution of the non-fibrillar components of the extracellular space of the heart to highlight the potential significance of these molecules in fibrosis, with direct evidence for some, although not all of these molecules in their direct contribution to fibrosis.