Lal Nathaniel, Chiu Amy Pei-Ling, Wang Fulong, Zhang Dahai, Jia Jocelyn, Wan Andrea, Vlodavsky Israel, Hussein Bahira, Rodrigues Brian
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and.
Rappaport Faculty of Medicine, Cancer and Vascular Biology Research Center, Technion, Haifa, Israel.
Am J Physiol Heart Circ Physiol. 2017 Jun 1;312(6):H1163-H1175. doi: 10.1152/ajpheart.00659.2016. Epub 2017 Mar 17.
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.
血管内皮生长因子B（VEGFB）在代谢活跃的组织中高度表达，如心脏和骨骼肌，提示其在维持这些组织的氧化代谢和收缩功能中发挥作用。多种心力衰竭模型显示VEGFB显著下降。然而，VEGFB降低在糖尿病性心肌病中是否起作用目前尚不清楚。在心肌细胞中的VEGFB中，有大量易于释放的池定位于细胞表面。对高糖的即时反应和内皮型乙酰肝素酶的分泌是这种表面结合的VEGFB的释放，其触发信号通路和基因表达以影响内皮细胞（自分泌作用）和心肌细胞（旁分泌作用）的存活。在高血糖条件下，当VEGFB产生受损时，血管内皮生长因子受体（VEGFR）-1表达会强劲增加，这可能是增强或维持VEGFB信号传导的一种机制。然而，即使糖尿病后VEGFR1增加，但心肌细胞仍无法对VEGFB作出反应。除了VEGFB产生和信号传导的丧失外，对负责VEGFB释放的蛋白——潜在乙酰肝素酶的评估还显示，慢性或急性糖尿病动物的全心脏中其表达也显著下降。在我们的糖尿病模型中，这些众多VEGFB途径的缺陷与细胞死亡特征增加有关。通过内皮细胞（分泌乙酰肝素酶）和心肌细胞（释放VEGFB）之间的这种双向相互作用，这种生长因子可以为糖尿病心脏提供抗细胞死亡保护，并且可能是延迟或预防心肌病的关键工具。我们发现内皮细胞（分泌乙酰肝素酶）和心肌细胞[释放血管内皮生长因子B（VEGFB）]之间存在双向相互作用。VEGFB通过ERK和细胞死亡基因表达促进细胞存活。VEGFB及其下游信号传导的丧失是高血糖后的早期事件，并随着疾病进展持续存在，这可以解释糖尿病性心肌病。
