Possible Mechanism of Human Recombinant Leptin-Induced VEGF A Synthesis via PI3K/Akt/mTOR/S6 Kinase Signaling Pathway while Inducing Angiogenesis: An Analysis Using Chicken Chorioallantoic Membrane Model

Abstract

<b><i>Introduction:</i></b> The present study aimed to realize human recombinant leptin ’s ability to synthesize VEGF A while inducing neovascularization through PI3K/Akt/mTOR/S6 kinase involved signaling pathway. <b><i>Methods:</i></b> To examine the PI3K/Akt/mTOR/S6 kinase pathway involvement in leptin-induced VEGF A synthesis, the chick chorioallantoic membrane (CAM) was incubated with human recombinant leptin and specific inhibitors of the proposed signaling molecules (rapamycin and wortmannin). We analyzed the role of specified signaling molecules in human recombinant leptin-induced physiological angiogenesis via VEGF A synthesis in detail with the support of various methodologies. <b><i>Results:</i></b> Human recombinant leptin’s ability to synthesize VEGF A is diminished significantly in the presence of inhibitors. This observation supported the role of PI3K/Akt/mTOR/S6 kinase signaling molecules in human recombinant leptin-mediated VEGF A synthesis while inducing angiogenesis in CAM. <b><i>Conclusion:</i></b> Synthesis of VEGF A, followed by the growth of new blood vessels, by human recombinant leptin via the activation of the PI3K/Akt/mTOR/S6 kinase signaling pathway reflects mechanistic therapeutic application of human recombinant leptin. The data also signify the role of mTOR and S6 kinase molecules in angiogenesis under a physiological environment.

Human Recombinant Leptin Shows Dose and Time-Dependent Release of Nitric Oxide from Endothelial Nitric Oxide Synthase in Endothelium While on Angiogenesis

“…Various ndings prompted that human recombinant leptin may serve as a regulatory factor for angiogenesis [3,4]. NO plays a critical role in angiogenesis and enhances multiple processes in ECs such as cell survival, proliferation, migration [13,14].…”

“…It also acts as a pro-angiogenic molecule and initiates the process of angiogenesis through the Ob-R receptor present on vascular endothelial cells (ECs) [2]. In our previous experiments we speculated that the human recombinant leptin could induce concentration and time dependent angiogenic potential and able to enhance the mRNA transcription level of Vascular Endothelial Growth Factor A (VEGF A) via PI3K/Akt/mTOR/s6Kinase signaling pathway on chick embryo vascular bed [3,4]. Leptin-induced NO releases from eNOS in ECs through the activation of various canonical signaling pathway is considered as one of the critical events in angiogenesis [5,6].…”

Biodiversity of the Adipocyte-Derived Hormone, Leptin

“…It is observed that Endothelial cells (ECs) express OB-R leptin receptors and the binding of leptin to OB-R enables the growth of small blood vessels [3]. Recently, it has been identified that leptin could induce PI3K/Akt/ mTOR/s6Kinase signaling pathway and enhance VEGF mRNA's transcription level while inducing angiogenesis [4]. One of the intriguing possibilities of leptin is that it promotes neovascularization through paracrine mode concerning the volume of fat mass [25].…”

“…It circulates through the bloodstream, engages with normal metabolism, regulates energetic homeostasis, reproductive system, and influences the circadian cycle, lipid inflammation, and carbohydrate mechanisms. Leptin is well known for its pro-angiogenic potential and operates multiple signaling agencies through the receptor located in endothelial cells [3,4]. Leptin is also secrets by other organs, such as the placenta, bone marrow, ovaries, stomach, and cellular structures, including mammary epithelial cells, P/D1 cells, and gastric chief cells [1].…”

Antiangiogenic Drugs in NASH: Evidence of a Possible New Therapeutic Approach

“…Leptin induces an increase in vascular permeability and potentiates VEGF-mediated angiogenesis dose-dependently [ 25 ]. Indeed, leptin induces the synthesis of VEGF-A by endothelial cells, and thus the growth of new blood vessels, via the activation of the PI3K/Akt/mTOR/S6 kinase signaling pathway [ 26 ].…”