CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage

Abstract

Visual Abstract

Improving Cerebrovascular Function to Increase Neuronal Recovery in Neurodegeneration Associated to Cardiovascular Disease

“…TNF-α-induced impairment of cerebrovascular function that associates to CBF deficits and secondary ischemia during SAH (Vecchione et al, 2009;Yagi et al, 2015) are thought to stem from altered S1P signaling as TNF-α alters S1P degradation, which leaves more S1P available for pro-constrictive S1PR2 signaling in mural cells (Figure 1). Improving S1P degradation normalized the perfusion deficits, reduced neuronal injury, and improved neurological function in this SAH model (Lidington et al, 2019).…”

“…Similarly, directly targeting S1P and its receptors bears considerable disadvantages due to its pleiotropy and cell-type specific functionality. Thus, correcting S1P homeostasis by normalizing S1P homeostasis (i.e., through stabilizing CFTR function) yielded beneficial effects (Lidington et al, 2019). Pharmacological treatment of HF mice improved neuronal integrity (i.e., dendritic lengths and spine density) and memory function through normalizing pathological alterations in cerebral artery CFTR expression, vascular reactivity, and CBF (Lidington et al, 2019).…”

“…Thus, correcting S1P homeostasis by normalizing S1P homeostasis (i.e., through stabilizing CFTR function) yielded beneficial effects (Lidington et al, 2019). Pharmacological treatment of HF mice improved neuronal integrity (i.e., dendritic lengths and spine density) and memory function through normalizing pathological alterations in cerebral artery CFTR expression, vascular reactivity, and CBF (Lidington et al, 2019). Targeting S1P-CFTR signaling, therefore, may emerge as valuable tool to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury contributing to HF-associated neurodegeneration and memory deficits.…”

“…The therapeutic window of tPA, however, is limited to 3-4.5 h post-stroke onset as tPA administration beyond 4.5 h increases the risk of developing edema and hemorrhagic transformation that in turn, is associated with delayed ischemia (Pena et al, 2017). Targeting vascular function and re-establishing proper CBF has been focus of many preclinical research efforts and yielded some promising results that warrant testing in humans (Iwasawa et al, 2018;Lidington et al, 2019).…”

“…Although the association between CVD and increased dementia risk is well established (Kuller et al, 2005;Jefferson et al, 2010;Gorelick et al, 2011;Haring et al, 2013), it is still unclear if treatments would reverse already established CI. Because of its intimate link to neuronal function, targeting the cerebral vasculature to improve CBF has yielded some promising results in respect to neuro-regenerative processes (Meissner et al, 2012;Lidington et al, 2019). This article summarizes vascular targets that have shown to attenuate neuronal degeneration or cognitive function associated to hypertension, HF and stroke by improving cerebrovascular function or CBF deficits.…”