Targeting cerebrovascular sphingosine‐1‐phosphate signaling to treat heart failure‐induced brain dysfunction

Abstract

Chronic cardiovascular diseases increasingly emerge as risk factors for neurodegeneration. Heart failure for instance, induces a chronic reduction in cerebral perfusion. Such chronic brain perfusion deficits are frequently accompanied by cognitive decline, which not only seriously impacts the patients’ quality of life but also reduces treatment compliance. Statistically, cognitive impairment is 5 times more prevalent in heart failure patients relative to the age‐matched general population. We previously demonstrated that heart failure associates to augmented signaling of a potent bioactive phospholipid called sphingosine‐1‐phosphate (S1P). During heart failure, such enhanced S1P signaling roots from dysfunctional cystic fibrosis transmembrane regulator (CFTR) expression and activity. CFTR controls the bioavailability of cerebrovascular S1P and hence, its pro‐constrictive effects. In heart failure, reduced microvascular CFTR expression correlates with enhanced myogenic tone and reduced cerebral blood flow.In this study, we investigated the therapeutic potential of CFTR corrector compounds to normalize cerebrovascular S1P signaling and thereby, improve neurological function during experimental heart failure in mice.Systemic CFTR corrector treatment stabilized cerebrovascular CFTR expression, improved myogenic tone and rectified deficient cerebral perfusion in heart failure, without altering the systemic parameters of cardiac output or total peripheral resistance. This normalization associated to recovery of neuronal integrity (i.e., dendrite morphology and dendritic spine density) and cognitive function. The heart failure‐associated dendrite atrophy (i.e., a 22% reduction in dendrite length) was not altered in mice treated with CFTR corrector compound. Longitudinal pre‐treatment (i.e., at 10 weeks post‐infarction) and post‐treatment analyses of the same vehicle‐ and CFTR corrector‐treated HF mice confirmed that CFTR corrector treatment reversed the impaired rhino‐cortical‐dependent, short‐term retention of object familiarity caused by heart failure.Our results put forward a new mechanistic understanding of heart failure‐associated brain complications, and CFTR correctors as potential treatment option for heart failure‐associated cognitive decline.Support or Funding InformationThis work is supported by the Knut & Alice Wallenberg Foundation and the Swedish Research Council.