The extracellular matrix and angiogenesis: Two aspects that define cardiovascular health and disease

Abstract

Two aspects that define cardiovascular health and disease are the extracellular matrix and angiogenesis. The extracellular matrix During development, ECM remodeling accompanies the formation of distinct tissues. This impact makes the ECM an ideal scaffold to mimic in tissue constructs for 3D cell models or for transplantation. Here, selection of the appropriate matrix is crucial, as it will profoundly affect cell behavior. In order to this, it is necessary to fully characterize the unique ECM composition of specific tissues during development. In this thesis, the differences between the fetal and mature human ECM was characterized in both the kidney and renal artery. This comparison revealed a specific ECM niche during renal development. This is valuable knowledge for improving current constructs to better mimic renal tissue. A critical difference found is the abundance of EMILIN1 in the fetal ECM of both tissues. This thesis shows that EMILIN1 is important for the degree of renal cell adhesion and thus has potential for the use in renal constructs. Dysregulation of ECM remodeling is associated with many diseases, including dilated cardiomyopathy (DCM). Myocardial fibrosis is a major feature of DCM and therefore it is inevitable that complex ECM remodeling is involved. This thesis describes the changes in ECM composition and associated remodeling pathways during DCM and it is likely that among these components are novel diagnostic markers or therapeutic targets. Angiogenesis VE-cadherin is indispensable for proper angiogenesis, as the amount of VE-cadherin at the plasma membrane is directly linked to endothelial barrier function. This bioavailability is regulated by endocytosis; however, little is known about the exact contribution of endocytic regulators. This thesis reports two novel proteins involved in regulating endocytosis during angiogenesis: CMTM3 and CMTM4. These proteins are involved in regulating the bioavailability of VE-cadherin on the plasma membrane by either stimulating the uptake from or recycling to the cell membrane. This novel fundamental finding holds promising therapeutic perspectives for angiogenic diseases. Dysregulation of angiogenesis contributes to many disorders, including chronic kidney disease (CKD). Genetic alterations have been linked to CKD and recent GWAS studies identified ±100 SNPs associated with CKD traits. Unfortunately, ±90% of these SNPs lie within the non-coding genome, including DNA regulatory regions (DREs). This thesis has linked DREs containing a CKD-associated SNP with their target genes using 4C-sequencing. These results further our understanding of the molecular mechanisms underlying CKD that can aid in the development of future biomarkers or therapies.