Angiogenic Factor AGGF1-Primed Endothelial Progenitor Cells Repair Vascular Defect in Diabetic Mice

Abstract

Hyperglycemia-triggered vascular abnormalities are the most serious complications of diabetes mellitus (DM). The major cause of vascular dysfunction in DM is endothelial injury and dysfunction associated with the reduced number and dysfunction of endothelial progenitor cells (EPCs). A major challenge is to identify key regulators of EPCs to restore DM-associated vascular dysfunction. We show that EPCs from heterozygous knockout Aggf1+/− mice presented with impairment of proliferation, migration, angiogenesis, and transendothelial migration as in hyperglycemic mice fed a high-fat diet (HFD) or db/db mice. The number of EPCs from Aggf1+/− mice was significantly reduced. Ex vivo, AGGF1 protein can fully reverse all damaging effects of hyperglycemia on EPCs. In vivo, transplantation of AGGF1-primed EPCs successfully restores blood flow and blocks tissue necrosis and ambulatory impairment in HFD-induced hyperglycemic mice or db/db mice with diabetic hindlimb ischemia. Mechanistically, AGGF1 activates AKT, reduces nuclear localization of Fyn, which increases the nuclear level of Nrf2 and expression of antioxidative genes, and inhibits reactive oxygen species generation. These results suggest that Aggf1 is required for essential function of EPCs, AGGF1 fully reverses the damaging effects of hyperglycemia on EPCs, and AGGF1 priming of EPCs is a novel treatment modality for vascular complications in DM.

Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases

“…A novel signaling pathway, that is, angiogenic factor with G patch and FHA domains 1 (AGGF1)‐Akt‐Fyn‐Nrf2‐antioxidative genes, was also involved in the regulation of diabetic EPC function. AGGF1 activated Akt signaling, which inhibited Fyn‐mediated export and degradation of nuclear Nrf2; Nrf2 then binded to the promoter and regulatory region and activated the transcription of CAT, HO‐1, and NQO‐1, which reduced oxidative stress and improved the ischemia‐reparative capacity of transplanted EPCs in diabetic mice (Yao et al, 2019).…”

Expression of angiogenic factor with G patch and FHA domains 1 (AGGF1) in placenta from patients with preeclampsia

“…Besides angiogenesis, AGGF1 has been suggested to be involved in multiple other functions. It has been suggested that AGGF1 can fully reverse the effects of hyperglycaemia on endothelial progenitor cells [32]. AGGF1 may also inhibit TNF-a-mediated monocyte adhesion to endothelial cells and affect the expression of adhesion molecules and chemokines [17].…”

Role of epigenetic m6A RNA methylation in vascular development:mettl3regulates vascular development through PHLPP2/mTOR‐AKT signaling

“…Cell proliferation assays for HUVECs were carried out using the Cell Counting Kit‐8 (Dojindo, Kumamoto, Japan) as described 27‐29 . Cell migration was assessed using Transwell cell migration assays and wound scratch cell migration assays as described 27,30 . Endothelial cell tube formation assays were carried out with HUVECs cultured in 6‐well plates and transfected with METTL3 siRNA or treated with cycloleucine (40 mmol/L) for 36 hours as described 27,30,31 …”