Loss of VEGFB and its signaling in the diabetic heart is associated with increased cell death signaling.
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.NEW & NOTEWORTHYWe 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.
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and.
Nathaniel
N
Lal
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and.
Amy Pei-Ling
AP
Chiu
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and.
Fulong
F
Wang
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and.
Dahai
D
Zhang
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and.
Jocelyn
J
Jia
Andrea
A
Wan
Rappaport Faculty of Medicine, Cancer and Vascular Biology Research Center, Technion, Haifa, Israel.
Israel
I
Vlodavsky
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and.
Bahira
B
Hussein
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada; and rodrigue@mail.ubc.ca.
Brian
B
Rodrigues
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D058065:Diabetic Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology; D005966:Glucuronidase / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D017208:Rats, Wistar; D015398:Signal Transduction; D013311:Streptozocin; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D000099175:Heparanase
D051017:Apoptosis Regulatory Proteins; D005966:Glucuronidase; D013311:Streptozocin; D042561:Vascular Endothelial Growth Factor B; D040281:Vascular Endothelial Growth Factor Receptor-1; D000099175:Heparanase; C581256:VEGFB protein, rat; C501164:Flt1 protein, rat
endothelial cell; heparanase; streptozotocin diabetes; vascular endothelial growth factor B