Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

Abstract

Accumulating evidence pinpoints sex differences in stroke incidence, etiology and outcome. Therefore, more understanding of the sex-specific mechanisms that lead to ischemic stroke and aggravation of secondary damage after stroke is needed. Our current mechanistic understanding of cerebral ischemia states that endothelial quiescence in neurovascular units (NVUs) is a major physiological parameter affecting the cellular response to neuron, astrocyte and vascular smooth muscle cell (VSMC) injury. Although a hallmark of the response to injury in these cells is transcriptional activation, noncoding RNAs such as microRNAs exhibit cell-type and context dependent regulation of gene expression at the post-transcriptional level. This review assesses whether sex-specific microRNA expression (either derived from X-chromosome loci following incomplete X-chromosome inactivation or regulated by estrogen in their biogenesis) in these cells controls NVU quiescence, and as such, could differentiate stroke pathophysiology in women compared to men. Their adverse expression was found to decrease tight junction affinity in endothelial cells and activate VSMC proliferation, while their regulation of paracrine astrocyte signaling was shown to neutralize sex-specific apoptotic pathways in neurons. As such, these microRNAs have cell type-specific functions in astrocytes and vascular cells which act on one another, thereby affecting the cell viability of neurons. Furthermore, these microRNAs display actual and potential clinical implications as diagnostic and prognostic biomarkers in ischemic stroke and in predicting therapeutic response to antiplatelet therapy. In conclusion, this review improves the current mechanistic understanding of the molecular mechanisms leading to ischemic stroke in women and highlights the clinical promise of sex-specific microRNAs as novel diagnostic biomarkers for (silent) ischemic stroke.

Exploratory Analysis of MicroRNA Alterations in a Neurodevelopmental Mouse Model for Autism Spectrum Disorder and Schizophrenia

“…Moreover, the miR-92a-2-5 showed opposing trends from females (reduced values) to males (enhanced values). This is in line with the wide scientific literature showing the association between sex differences and miRNA expression in numerous disorders, including cancer, diabetes mellitus type 2, or ischemic stroke [ 111 , 112 , 113 ]. Furthermore, sex differences in mental disorders or conditions, including SCZ and ASD, are among the most intriguing and stable findings in psychiatry [ 114 ].…”

Sex-Biased Expression and Response of microRNAs in Neurological Diseases and Neurotrauma

“…For example, miR-509-3p levels were increased in males and decreased in females, and miR-883b-3p levels were decreased in males and elevated in females [ 90 ]. Florijn et al have shown that several X-linked and estrogen-regulated miRNAs were expressed in the neurovascular unit and may play a role in sex-specific responses to ischemic stroke [ 130 ]. However, it remains speculative as to whether these miRNAs exhibit a sexually dimorphic response to ischemic stroke, and these issues will need to be further examined.…”

Deciphering Post-Stroke Sleep Disorders: Unveiling Neurological Mechanisms in the Realm of Brain Science

“…After cerebral ischemia, NVUs and their microvessels undergo diverse extents of injury [87]. This phenomenon encompasses structural alterations and related cellular dysfunctions, which subsequently influence the regulation of cerebral blood flow [88]. Consequently, these affect neural functioning and sleep patterns.…”