GLP-1 promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the Akt, Src and PKC pathways.

Metabolism : clinical and experimental

PubMedID: 23684008

Aronis KN, Chamberland JP, Mantzoros CS. GLP-1 promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the Akt, Src and PKC pathways. Metab Clin Exp. 2013;62(9):1279-86.
INTRODUCTION
Novel anti-diabetic medications that mimic or augment the physiological actions of GLP-1 improve cardiovascular risk factors in diabetics and GLP-1 has been proposed to have a beneficial role in the cardiovascular system. GLP-1 may have a direct cardioprotective role by decreasing infarct size and protecting from ischemia-reperfusion injury while prolonging survival in rodent models. The mechanisms underlying these observations remain largely unknown. In vitro studies suggest that GLP-1 may promote endothelial cell proliferation, but no study to date has evaluated a potential direct effect of GLP-1 on angiogenesis.

SPECIFIC AIM
To evaluate whether GLP-1 affects angiogenesis in humans and to elucidate underlying molecular mechanisms.

MATERIAL AND METHODS
We utilized a 3D culture system where spherules of human umbilical vein endothelial cells (HUVECs) embedded in a collagen scaffold were treated with escalating doses of human recombinant GLP-1 (50-2000nmol/L) and the formation of new vessels was observed and quantified. Signaling inhibitors were utilized to identify molecular pathways through which GLP-1 promotes angiogenesis.

RESULTS
We demonstrate that GLP-1 promotes angiogenesis in a dose-dependent manner. The maximum effect on angiogenesis was observed at a GLP-1 dose of 500nmol/L, while increased angiogenesis occurred in response to doses ranging from 200nmol/L to 1000nmol/L. Pre-treatment of the system with Akt inhibitor IV, Bisindolylmaleimide (PKC inhibitor) and src inhibitor I resulted in a significant decrease of the GLP-1 induced angiogenesis.

CONCLUSIONS
This is the first study to demonstrate that GLP-1 promotes angiogenesis in a HUVEC three dimensional in vitro model. This effect requires pharmacological doses and is mediated through the Akt, PKC and src pathways.