Vascular Endothelial Growth Factor B and Its Signaling

Abstract

In diabetes, compromised glucose utilization leads the heart to use FA almost exclusively for ATP generation. Chronically, this adaptation unfortunately leads to the conversion of FA to potentially toxic FA metabolites. Paired with increased formation of reactive oxygen species related to excessive mitochondrial oxidation of FA, can provoke cardiac cell death. To protect against this cell demise, intrinsic mechanisms must be available to the heart. Vascular endothelial growth factor B (VEGFB) may be one growth factor that plays an important role in protecting against heart failure. As a member of the VEGF family, initial studies with VEGFB focused on its role in angiogenesis. Surprisingly, VEGFB does not appear to play a direct role in angiogenesis under normal conditions or even when overexpressed, but has been implicated in influencing vascular growth indirectly by affecting VEGFA action. Intriguingly, VEGFB has also been shown to alter gene expression of proteins involved in cardiac metabolism and promote cell survival. Conversely, multiple models of heart failure, including diabetic cardiomyopathy, have indicated a significant drop in VEGFB. In this review, we will discuss the biology of VEGFB, and its relationship to diabetic cardiomyopathy.

Keywords: STZ diabetes; VEGFB; angiogenesis; cardiomyopathy; cell death.

FIGURE 1

Differential functions of vascular endothelial growth factor receptors. VEGFA binding to VEGFR1 does not produce significant receptor activation (in this case the receptor acts a decoy), whereas VEGFB binding to VEGFR1 has been described to promote cell survival. VEGFA can also bind to VEGFR2, albeit with a lower affinity, but this is considered a key regulator of angiogenesis, promoting endothelial cell migration and proliferation.

FIGURE 2

Alternative splicing of VEGFB. Alternative splicing leads to two isoforms. VEGFB₁₆₇ encompasses over 80% of transcripts and contains a highly basic C-terminal heparin binding domain allowing it to be sequestered onto the cell surface. The other isoform, VEGFB₁₈₆ has a hydrophobic C-terminal making it freely soluble.

FIGURE 3

Cardio protective actions of VEGFB. Although it does not play a direct role in angiogenesis, VEGFB has been implicated in increasing capillary diameter and artery size. Additionally, VEGFB has a significant role in protecting against cell death and promoting adaptive hypertrophy.

FIGURE 4

Indirect role of VEGFB in angiogenesis. VEGFR1 has a 10× fold greater affinity for binding VEGFA than VEGFR2 (left panel). Overexpression of VEGFB is suggested to occupy and thus displace VEGFA from VEGFR1. This allows more VEGFA to bind to VEGFR2 and can initiate angiogenesis (right panel).