Browsing by discipline "Kärlbiologi"

The heart acts as a muscular pump in the hub of closed blood vascular circulatory loop to transport oxygenated blood and nutrients to various organs and collecting the deoxygenated blood back to the right ventricle for re-oxygenation in the lungs. Indigenously, the heart consists of two major cell populations; myocytes (cardiomyocytes) and non-myocytes (endothelial cells, vascular smooth muscle cells, pericytes, fibroblasts, leukocytes, pace maker cells and purkinje fibers) contributing to the structure and normal function of the heart. The presence of abundant endothelial cells, bi-directional paracrine communication between endothelial cells (ECs) and cardiomyocytes (CMCs), secretory properties of ECs regulating the heart growth, metabolism, maintaining blood vessel homeostasis and vascular tone further augments the indispensable role of cardiac ECs (Pinto, A.R. et al., 2016, Aird, W.C., 2007 and 2012). The Vascular Endothelial Growth Factors (VEGFs) and VEGF receptors (VEGFRs) play a crucial role in the development and maintenance of cardiovascular system. Previous findings have demonstrated the critical role of VEGFR1 during embryogenesis and its absence is embryonically lethal (Fong, G.H. et al., 1995; Fong, G.H. et al., 1999). Global deletion of VEGFR1 in adult mice, in turn, resulted in increased angiogenesis of various organs like heart, liver, lungs, kidney and brain (Ho, V.C. et al., 2012). However, the cell specific role (physiological and pathological) of VEGFR1 in the adult mouse heart remains unknown. In this study, I first assessed and validated the endothelial specificity of PdgfbCreERT2-Cre line in adult mice by crossing it with Td-Tomato reporter mouse line. Then we crossed PdgfbCreERT2 mice with VEGFR1 floxed mice, and after tamoxifen treatment, the recombination and deletion efficiency were analyzed in the heart. We also treated mice with AAV9-VEGF-B, which is a ligand for VEGFR1. Effects on cardiac vasculature and cardiomyocyte growth were analyzed. The findings of this thesis demonstrate that both deletion of endothelial VEGFR1 and overexpression of VEGF-B induce angiogenesis and modest cardiac hypertrophy in the heart. Mechanistically, this was mediated by activation of VEGFR2 pathway, as the effects were blocked by VEGFR2 antibody treatment. In conclusion, activation of VEGFR2 in cardiac endothelial cells by releasing its endogenous ligand VEGF from its decoy receptor VEGFR1 leads to angiogenesis and physiological cardiac hypertrophy.