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.
Highlights
These effects were mediated via AdamTs1 which plasma levels were increased in atherosclerotic patients compared to controls [68]
This study identified that overexpressing miR-542-3p in young vascular smooth muscle cell (VSMC) suppressed their osteogenic differentiation induced by β-glycerophosphate (β-GP, an in vitro model of VSMC calcification) via a reduction of bone morphogenetic protein 7 (BMP7, a protein known for inducing osteogenesis and chondrogenesis) expression
We conclude that (i) sex-specific microRNAs performed cell-type and context dependent regulation of gene expression in neurovascular units (NVUs); (ii) sex-specific microRNAs in vascular cells and neurons act on one another, and as such, affect the cell viability of neurons
Summary
Accumulating evidence suggests that there are sex differences in stroke, in terms of incidence and clinical presentation, etiology, and outcome. Mechanistic studies into more female-specific trends in acute stroke have demonstrated that compared to men, women have a different profile of vascular risk factors (more hypertension, atrial fibrillation, heart failure, valvular heart disease and obesity), a different distribution of stroke subtypes (more cardio-embolic stroke) and a different outcome (worse early outcome, more disability, longer hospital stay and higher in-hospital mortality) [2]. Stroke in women is driven by divergent risk factors Stroke in women is driven by divergent risk factors fibrillation and cardio-embolism) compared to stroketoinstroke men (atherosclerosis and internal (atrial fibrillation and cardio-embolism) compared in men (atherosclerosis and carotid artery disease). Given the higher likelihood of disability and worse quality of life stroke diagnosis in women, early recognition [5].
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