Metabolite control of angiogenesis: angiogenic effect of citrate

Abstract

Endothelial cells respond to hypoxic changes with resultant accumulation of several metabolites and switch over to angiogenic phenotype. Although certain intermediates of glycolytic and oxidative metabolic pathways have been known to affect angiogenesis, the effect of citrate, which accumulates in certain tumors, on angiogenesis is not known. Therefore, the effect of citrate on angiogenesis was studied using different model systems. Increased vascularization in chorioallantoic membrane assay, increased endothelial sprouting in rat aortic rings, and increased expression of CD31, E-selectin in endothelial cells suggested a possible proangiogenic effect of citrate. Upregulation of angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor suggested that the effect of citrate involves modulation of expression of angiogenic growth factors. LY 294002, an inhibitor of PI3K-Akt pathway, and wortmannin, an inhibitor of Akt pathway, reversed the effect of citrate in human umbilical vein endothelial cells. Citrate induced significant upregulation and activation of Akt in endothelial cells. Rapamycin, an inhibitor of mTOR, also reversed the effect of citrate in human umbilical vein endothelial cells and sprouting of aortic rings suggesting that the angiogenic effect of citrate involves activation of PI3K-Akt-mTOR pathway.

Platelets Facilitate the Wound-Healing Capability of Mesenchymal Stem Cells by Mitochondrial Transfer and Metabolic Reprogramming

“…´nez- Reyes and Chandel, 2020;McDonnell et al, 2016). Therefore, accumulation of citrate and fatty acids in MSCs in response to incubation with platelets promotes the expression and secretion of pro-angiogenic factors, as previously reported for endothelial or cancer cells (Binu et al, 2013;Bruning et al, 2018;Frezza, 2017;Zhou et al, 2016).…”

“…In particular, we show that mitochondria derived from platelets activate the TCA cycle in the recipient MSCs, resulting in an increased amount of several metabolites. (legend continued on next page) ll Article Of particular interest is citrate that has been critically implicated in the pro-angiogenic process (Binu et al, 2013).…”

The Secretome of Endothelial Progenitor Cells Promotes Brain Endothelial Cell Activity through PI3-Kinase and MAP-Kinase

“…Hence, in the present study it cannot be excluded that non-proteiceous compounds might participate at least in part in influencing the endothelial cell activity reported here. Among the different molecules that can be found in the conditioned medium, the compounds of the cellular metabolism as citrate [39], ATP [40] or 20-Hydroxyeicosatetraenoic acid (20-HETE, an eicosanoid) [41] have been shown to promote angiogenesis directly activating AKT and ERK or synergizing growth factors action. Hence, the dissection of conditioned medium components and signaling pathway activation in target cells can be considered the two sides of the same coin.…”

Citrate chemistry and biology for biomaterials design

“…Excitingly, soluble citrate released from citrate-based materials during degradation, after supplemented in osteogenic medium, has been found to elevate the alkaline phosphatase (ALP) of osteoblast-like MG63 cells [72] and to increase the calcium nodule formation of human mesenchymal stem cells (hMSCs) [135]. In addition, solute citrate has shown angiogenic effect on endothelial cells in terms of promoting endothelial sprouting in rat aortic rings, and increasing the production of angiogenic growth factors, VEGF and FGF [136]. Given that bone formation involves the differentiation of hMSCs to bone-forming osteoblasts producing a large amount of bone matrix, and involves the formation of new blood vessels transporting growth factors and nutrients, all the results support the notion that citrate may also have an indispensable yet unexplored impact on bone formation, meanwhile support the use of citrate in bone biomaterial design.…”