Loss of VEGFB and its signaling in the diabetic heart is associated with increased cell death signaling

Abstract

Vascular endothelial growth factor B (VEGFB) is highly expressed in metabolically active tissues, such as the heart and skeletal muscle, suggesting a function in maintaining oxidative metabolic and contractile function in these tissues. Multiple models of heart failure have indicated a significant drop in VEGFB. However, whether there is a role for decreased VEGFB in diabetic cardiomyopathy is currently unknown. Of the VEGFB located in cardiomyocytes, there is a substantial and readily releasable pool localized on the cell surface. The immediate response to high glucose and the secretion of endothelial heparanase is the release of this surface-bound VEGFB, which triggers signaling pathways and gene expression to influence endothelial cell (autocrine action) and cardiomyocyte (paracrine effects) survival. Under conditions of hyperglycemia, when VEGFB production is impaired, a robust increase in vascular endothelial growth factor receptor (VEGFR)-1 expression ensues as a possible mechanism to enhance or maintain VEGFB signaling. However, even with an increase in VEGFR1 after diabetes, cardiomyocytes are unable to respond to VEGFB. In addition to the loss of VEGFB production and signaling, evaluation of latent heparanase, the protein responsible for VEGFB release, also showed a significant decline in expression in whole hearts from animals with chronic or acute diabetes. Defects in these numerous VEGFB pathways were associated with an increased cell death signature in our models of diabetes. Through this bidirectional interaction between endothelial cells (which secrete heparanase) and cardiomyocytes (which release VEGFB), this growth factor could provide the diabetic heart protection against cell death and may be a critical tool to delay or prevent cardiomyopathy. We discovered a bidirectional interaction between endothelial cells (which secrete heparanase) and cardiomyocytes [which release vascular endothelial growth factor B (VEGFB)]. VEGFB promoted cell survival through ERK and cell death gene expression. Loss of VEGFB and its downstream signaling is an early event following hyperglycemia, is sustained with disease progression, and could explain diabetic cardiomyopathy.

VEGFB‐VEGFR1 ameliorates Ang II‐induced cardiomyocyte hypertrophy through Ca2+‐mediated PKG I pathway

“…33 Under conditions of hyperglycemia, when VEGFB production is impaired, a robust increase in vascular endothelial growth factor receptor (VEGFR)-1 expression ensues as a possible mechanism to enhance or maintain VEGFB signaling. 34 Here, we further investigated the role of two types of VEGFRs: VEGFR1 and VEGFR2, in the anti-hypertrophy effect of VEGFB. Consistent with earlier results, VEGFB attenuated the Ang II-induced disorders in cardiomyocytes; however, after VEGFR1 knockdown, these improving effects of VEGFB were partially abolished, as exhibited by the elevated Ca 2+ content and elevated β-MHC, BNP, and AMP protein levels.…”

Guidelines for experimental models of myocardial ischemia and infarction

“…Finally, the overwhelming majority of studies conducted to date have assessed the efficacy of candidate cardioprotective strategies using healthy, juvenile, or adult animals. There is evidence that the infarct-sparing effect of these purportedly protective interventions may be lost or attenuated in the setting of clinically relevant comorbidities, including aging, type 1 and type 2 diabetes, hypercholesterolemia, and hypertension, and may be influenced by diet or exercise ( 3 , 4 , 51 , 78 , 115 , 117 , 146 , 150 , 186 , 197 , 246 , 249 , 321 ). Accordingly, once proof of principle is established, it is imperative that promising cardioprotective therapies be reevaluated, adhering to the essential elements of rigor described above, in comorbid models ( 127 ).…”

Vascular Endothelial Growth Factor B and Its Signaling

“…These animals were kept for 6 weeks, a well-established model of diabetic cardiomyopathy. Analysis of cardiomyocyte VEGFB protein and mRNA expression revealed a significant decrease in the production of this growth factor ( 68 ). Furthermore, there was reduced cell survival signaling as well as a corresponding increase in cell death markers such as cleaved caspase 3 and cleaved PARP.…”