Mechanical Stress Regulates Endothelial Progenitor Cell Angiogenesis Through VEGF Receptor Endocytosis

Abstract

SummaryThe clinical goal of cell-based treatment for chronic heart failure is to coordinately reconstitute the cardiomyocytes and associated circulation environment including coronary resistance arteries, arterioles, and capillary profiles.1) This goal can be possibly achieved by implementing multipotent adult stem cells. However, it remains a challenge to modify the capillary network in the decompensated heart. A mechanical stress model was used in this study to mimic the hemodynamic and hormonal states of the decompensated heart in vitro. The angiogenesis role of endothelial progenitor cells (EPCs) under stress has been well-recognized in vascular repair. We investigated the molecular mechanisms of EPCs in this model. We found that expression of vascular endothelial growth factor (VEGF) in EPCs was significantly decreased by mechanical stress, and this effect was accompanied by a decrease in angiogenesis in vitro. Interestingly, the defective angiogenesis can be reversed by upregulating the membrane VEGF receptor (VEGFR) endocytosis. An atypical protein kinase C (aPKC) inhibitor can promote the VEGFR internalization in EPCs and enhance the formation of vascular networks. Thus, the upregulation of VEGFR endocytosis in EPCs could be a potential therapy for the cell-based treatment of chronic heart failure by enhancing the cardiomyocytes. (Int Heart J 2016; 57: 356-362) Key words: Cell-based treatment, Capillary network I n the last decade, several types of cells have been utilized in cell-based therapies to treat acute myocardial infarction and chronic heart failure (CHF). Endothelial progenitor cells (EPCs) are a useful cell type that has been tested experimentally in patients with encouraging results.2-6) Kocher, et al 7) infused freshly isolated human EPCs into a nude rat model of myocardial ischemia and observed preservation of left ventricular (LV) function and inhibition of cardiac apoptosis. More than 10 clinical trials [4][5][6][8][9][10][11][12][13][14] have been performed to elucidate the therapeutic effects of EPCs. These studies have provided information regarding the feasibility of using EPCsbased therapy to promote vasculogenesis. Despite these promising results, the search for a means to reverse the negative remodeling associated with CHF remains a concern. 15) This search is complicated by numerous factors that influence the growth and behavior of harvested cells. These factors include the age of the organ, the pathological state, and the severity of the cardiac disease. 16,17) Additionally, insufficient oxygen supply provided by the existing capillary network further complicates the extent of the therapeutic benefit provided by stem/progenitor cells. Editorial p.268Currently, the means of modifying the regeneration and integrity of the capillary network in the failing and hypertrophied decompensated heart are limited clinically, and the underlying mechanism remains unclear. The viability, proliferation, migration, and angiogenesis of EPCs are four critical determinants of revascularization in...

Bevacizumab-Related Microvascular Angina and Its Management with Nicorandil

“…We and others have known that VEGF-A signaling plays a critically important role in maintaining the integrity of vascular endothelial cells. [8][9][10] MICROVASCULAR ANGINA RELATED TO BEVACIZUMAB REGIME Therefore, it could be speculated that a bevacizumabmediated suppression of endothelial VEGF-A signaling elicited endothelial dysfunction, resulting in the occurrence of hypertension and microvascular angina. Further research is needed to elucidate the molecular link between VEGF-A signaling and the microvascular circulation.…”

Does Mechanical Stress Regulate the Angiogenic Profile of Endothelial Progenitor Cells?

“…Bai, et al shed light on mechanical stretch, an important contributor to the development of cardiac hypertrophy and heart failure, 8,9) which elicits EPC dysfunction through induction of apoptosis and inhibition of proliferation and migration, ultimately leading to angiogenic failure. Bai, et al first isolated CD133 + CD34 + EPCs from human umbilical cord blood and validated EPC characteristics, including uptake of acetylated low-density lipoprotein, lectin binding, and expression of endothelial cell markers, CD31, and von Willebrand Factor (vWF).…”

“…Bai, et al first isolated CD133 + CD34 + EPCs from human umbilical cord blood and validated EPC characteristics, including uptake of acetylated low-density lipoprotein, lectin binding, and expression of endothelial cell markers, CD31, and von Willebrand Factor (vWF). 8) Cells were then subjected to mechanical stretch, a well-established model of mechanical stress in the pressureoverloaded heart. 9) Protein expression profiles revealed that mechanical stretch induced an increase in the pro-apoptotic factor Bax and a decrease in the anti-apoptotic factor Bcl2.…”

“…The discovery of a notable decrease of VEGF expression in mechanically stretched EPCs led Bai, et al to examine VEGF endocytosis as a mechanism by which EPCs lose their angiogenic properties. 8) As the importance of endocytosis in VEG-FR signaling and angiogenesis has been reported in the developing eye, 10) Bai, et al performed immunostaining for VEGFR to determine if the endocytosis of VEGFR was relevant to the mechanical stretch-induced inhibition of angiogenesis. 8) Under normal conditions, EPCs indeed demonstrated an accumulation of VEGFR in the perinuclear region, indicating activation of VEGFR signaling via endocytosis.…”

“…8) As the importance of endocytosis in VEG-FR signaling and angiogenesis has been reported in the developing eye, 10) Bai, et al performed immunostaining for VEGFR to determine if the endocytosis of VEGFR was relevant to the mechanical stretch-induced inhibition of angiogenesis. 8) Under normal conditions, EPCs indeed demonstrated an accumulation of VEGFR in the perinuclear region, indicating activation of VEGFR signaling via endocytosis. However, this accumulation of VEGFR was abrogated by mechanical stretch, implying a mechanical stress-induced inhibition of VEGFR endocytosis.…”