Leptin Promotes Angiogenesis via Pericyte STAT3 Pathway upon Intracerebral Hemorrhage

Abstract

Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin potentiates angiogenesis and plays a beneficial role in stroke. However, the proangiogenic effect of leptin on ICH has not been adequately explored. Moreover, leptin triggers post-ICH angiogenesis through pericyte, an important component of forming new blood vessels, which remains unclear. Here, we reported that exogenous leptin infusion dose-dependent promoted vascular endothelial cells survival and proliferation at chronic stage of ICH mice. Additionally, leptin robustly ameliorated pericytes loss, enhanced pericytes proliferation and migration in ICH mice in vivo, and in ICH human brain microvascular pericytes (HBVPC) in vitro. Notably, we showed that pericytes-derived pro-angiogenic factors were responsible for enhancing the survival, proliferation and tube formation followed leptin treatment in human brain microvascular endothelial cells (HCMEC/D3)/HBVPC co-culture models. Importantly, considerable improvements in neurobehavioral function and hostile microenvironment were observed in leptin treatment ICH mice, indicating that better vascular functionality post ICH improves outcome. Mechanistically, this study unveiled that leptin boost post-ICH angiogenesis potentially through modulation of leptin receptor (leptinR)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pericyte. Thus, leptin may be a lucrative option for the treatment of ICH.

Pathological mechanisms and future therapeutic directions of thrombin in intracerebral hemorrhage: a systematic review

“…Angiogenesis is an essential endogenous brain self-repair process for neurological recovery after ICH ( Cui et al, 2022 ). According to recent studies, low thrombin doses administered in the ICH rat model increase pericyte coverage by activating the angiopoietin receptor (Tie2) and downstream PI3K/Akt signaling, and the increased pericyte coverage subsequently promotes the maturation and stabilization of new vessels, alleviating neurological dysfunction and neuronal injury post-ICH ( Hu et al, 2019a ).…”

EAAT3 impedes oligodendrocyte remyelination in chronic cerebral hypoperfusion‐induced white matter injury

“…After BCAS surgery, mice were intracerebroventricular (AP: −0.5 mm, L: −1.0 mm, V: −2 mm) injected with saline or L‐trans‐2,4‐pyrrolidine dicarboxylate (PDC, P7575; Sigma; 0.8 μg in 2 μL saline per day) continuously for 14 days 29 . To study cell proliferation, mice were injected with EdU (5 mg/kg, in saline, C00053; RiboBio Co., Ltd.) for seven consecutive days following the modeling, with a 12‐h gap between each injection 30 . Animals were injected with rapamycin (Rap, AY‐22989; MCE) at a dose of 10 mg/kg once a day for 14 days.…”

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

“…An increase in STAT3 also mediates the effect of leptin in promoting angiogenesis after hemorrhage. Leptin infusion promoted a dose-dependent effect on vascular endothelial cell survival and proliferation after intracerebral hemorrhage in rodents [ 8 ].…”

“…Leptin is not only linked to physiological processes, but it is also involved in pathological situations. It is suggested to have anti-apoptotic and pro-angiogenetic effects [ 8 ] and to promote proliferation, cell survival and migration in physiological conditions, processes that may also affect the initiation and progression of different diseases, especially cancers of the brain, breast, or lung [ 9 ].…”