Angiogenic Endothelial Cell Signaling in Cardiac Hypertrophy and Heart Failure

Abstract

Endothelial cells are, by number, one of the most abundant cell types in the heart and active players in cardiac physiology and pathology. Coronary angiogenesis plays a vital role in maintaining cardiac vascularization and perfusion during physiological and pathological hypertrophy. On the other hand, a reduction in cardiac capillary density with subsequent tissue hypoxia, cell death and interstitial fibrosis contributes to the development of contractile dysfunction and heart failure, as suggested by clinical as well as experimental evidence. Although the molecular causes underlying the inadequate (with respect to the increased oxygen and energy demands of the hypertrophied cardiomyocyte) cardiac vascularization developing during pathological hypertrophy are incompletely understood. Research efforts over the past years have discovered interesting mediators and potential candidates involved in this process. In this review article, we will focus on the vascular changes occurring during cardiac hypertrophy and the transition toward heart failure both in human disease and preclinical models. We will summarize recent findings in transgenic mice and experimental models of cardiac hypertrophy on factors expressed and released from cardiomyocytes, pericytes and inflammatory cells involved in the paracrine (dys)regulation of cardiac angiogenesis. Moreover, we will discuss major signaling events of critical angiogenic ligands in endothelial cells and their possible disturbance by hypoxia or oxidative stress. In this regard, we will particularly highlight findings on negative regulators of angiogenesis, including protein tyrosine phosphatase-1B and tumor suppressor p53, and how they link signaling involved in cell growth and metabolic control to cardiac angiogenesis. Besides endothelial cell death, phenotypic conversion and acquisition of myofibroblast-like characteristics may also contribute to the development of cardiac fibrosis, the structural correlate of cardiac dysfunction. Factors secreted by (dysfunctional) endothelial cells and their effects on cardiomyocytes including hypertrophy, contractility and fibrosis, close the vicious circle of reciprocal cell-cell interactions within the heart during pathological hypertrophy remodeling.

Single-Cell RNA Sequencing of the Cardiovascular System: New Looks for Old Diseases

“…This heterogeneity could contribute to the variability of outcomes seen post-myocardial infarction in our patient population (81,82). Additionally, areas of myocardial damage after infarction are known to undergo angiogenesis in response to chronic hypoxic stress associated with subsequent fibrosis formation (82,83). Therefore, the formation of the coronary vasculature and its associated microvasculature could be of significant clinical importance.…”

Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt

“…Cardiac hypertrophy (CH) represents an adaptive response of the heart to an increased workload, and is also a well-established risk factor for cardiovascular mortality worldwide 1 . A multitude of factors, such as thyroid disorders, weakening of heart muscles, abnormal heart beat, protein deposition in the heart, mutations in sarcomeric proteins, and anemia, are known to contribute to CH 2 .…”

Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics

“…Heart failure (HF), a global pandemic present in 1-2% of the adult population, is caused by pathological changes in structural and/or functional properties of the cardiomyocytes, cardiac interstitium, or both [1,2]. Apart from pure haemodynamic overload, the progression of HF involves abnormal biochemical signalling of neurohormones, inflammatory cytokines and receptor tyrosine kinases (RTK), culminating into aberrant cardiac vascularisation and maladaptive left ventricular remodelling [2][3][4].…”