**6. Leptin as a pro-angiogenic factor**

In 1998, Sierra-Hongmans reported that vascular endothelial cells express leptin receptors, especially the long-form. This discovery leads to an insight into the role of leptin in angiogenesis [57]. The angiogenic impact of leptin was conformed used on in vitro and in vivo models analysis [3, 58]. Jin et al. proved that leptin could induce

angiogenesis in the cornea of the Zucker obese rat model through the activation of the Ob-R gene [59]. Leptin exerts a paracrine mode of action in tissues and activates various signaling during the promotion of angiogenesis. This endocrine hormone activates Akt signaling pathway and mediates NO-induced vasodilation [60]. In endothelial cell migration, leptin signals through the ERK pathway and activates the PI3k, Akt, and eNOS molecules. By stimulating the local neovascularization in adipose tissue, leptin promotes its release into the vascular system. This process enhances fatty acid oxidation and supports maintaining a proper balance between adipose tissue's fat deposits and blood supply [61]. Even though the vascular fenestration capacity of leptin is poorly understood, the effect is found similar to VEGF [62]. Leptin plays a crucial role in exchanging nutrients between the fetus and maternal circulation in the placenta via enhancing vascular permeability and could induce angiogenesis in the placenta [61].
