DRG2 결핍에 의한 혈관 내피세포 노화 및 기능 저하 연구

Abstract

Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, detailed mechanisms involved in endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced blood flow in the cerebral brain and reduced lung blood vessel density. We also found that DRG2 deficiency reduced the angiogenic capability of endothelial cells determined by matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype, including decreased cell growth, and enhanced level of p21 and phosphorylated p53, γH2AX, senescence-associated 𝛽-galactosidase (SA-𝛽-gal) activity, and SASP cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and reactive oxygen species (ROS) production. Induction of SA-𝛽-gal activity was prevented by the antioxidant N-acetyl cysteine (NAC) in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and downregulation of DRG2 is likely involved in vascular dysfunction and vascular diseases. In summary, we demonstrated that DRG2 deficiency induced endothelial dysfunction such as reduced blood flow and decrease in angiogenesis in vivo, ex vivo, and in vitro. DRG2 deficiency increased ROS production in endothelial cells through eNOS uncoupling and induced endothelial senescence. The enhanced endothelial senescence may contribute to the dysfunction found in DRG2-deficient endothelium. Even though we did not determine whether DRG2–/– mice showed enhanced frequency of vascular diseases, it is possible that DRG2 deficiency may increase ROS and thus endothelial dysfunction and lead to vascular diseases. Further studies are required to explore in more detail the roles of DRG2 in DNA damage, endothelial senescence, and vascular diseases.