Abstract
Maintenance of cerebral blood vessel integrity and regulation of cerebral blood flow ensure proper brain function. The adult human brain represents only a small portion of the body mass, yet about a quarter of the cardiac output is dedicated to energy consumption by brain cells at rest. Due to a low capacity to store energy, brain health is heavily reliant on a steady supply of oxygen and nutrients from the bloodstream, and is thus particularly vulnerable to stroke. Stroke is a leading cause of disability and mortality worldwide. By transiently or permanently limiting tissue perfusion, stroke alters vascular integrity and function, compromising brain homeostasis and leading to widespread consequences from early-onset motor deficits to long-term cognitive decline. While numerous lines of investigation have been undertaken to develop new pharmacological therapies for stroke, only few advances have been made and most clinical trials have failed. Overall, our understanding of the acute and chronic vascular responses to stroke is insufficient, yet a better comprehension of cerebrovascular remodeling following stroke is an essential prerequisite for developing novel therapeutic options. In this review, we present a comprehensive update on post-stroke cerebrovascular remodeling, an important and growing field in neuroscience, by discussing cellular and molecular mechanisms involved, sex differences, limitations of preclinical research design and future directions.
Highlights
Specialty section: This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology
(2) Tight junction breakdown. – Secretion of MMPs by pericytes, Endothelial cells (ECs), and microglia promotes degradation of the basement membrane and tight’ junctions (TJs) disruption, leading, to increased blood–brain barrier (BBB) permeability and edema. – Secreted MMPs facilitate angiogenesis and vascular remodeling by promoting EC and pericyte migration. – Basement membrane fibrosis induced by TGF-β. – Astrocytes contribute to glial scar formation which is both beneficial and detrimental to nearby cells. – Astrocytes upregulate glial fibrillary acidic protein (GFAP) soon after stroke and secrete neurotrophic and proangiogenic factors. – Pericytes secrete trophic factors that contribute to astrogliosis. – Leakage of blood-borne factors into brain parenchyma results in rapid microglia activation that enwrap and phagocytose ECs in the peri-infarct region
– ECs proliferate around hematoma following intracerebral hemorrhage (ICH). – BBB breakdown and tight junction disruption. – Blood in parenchyma results in rapid microglia activation to a pro-inflammatory phenotype, which eventually polarize to an anti-inflammatory phenotype. – Mutations in genes that encode basement membrane proteins are associated with ICH. – Loss of astrocyte-derived basement membrane proteins is associated with hemorrhagic stroke in deep brain regions. – MMP-9 implicated in hemorrhagic transformation following treatment for ischemic stroke. – Vascular endothelial growth factor (VEGF) can increase BBB permeability, which may help peripheral macrophages infiltrate into the brain
Summary
Edited by: Fabrice Dabertrand, University of Colorado School of Medicine, United States. Maintenance of cerebral blood vessel integrity and regulation of cerebral blood flow ensure proper brain function. Due to a low capacity to store energy, brain health is heavily reliant on a steady supply of oxygen and nutrients from the bloodstream, and is vulnerable to stroke. By transiently or permanently limiting tissue perfusion, stroke alters vascular integrity and function, compromising brain homeostasis and leading to widespread consequences from early-onset motor deficits to long-term cognitive decline. Our understanding of the acute and chronic vascular responses to stroke is insufficient, yet a better comprehension of cerebrovascular remodeling following stroke is an essential prerequisite for developing novel therapeutic options. We present a comprehensive update on post-stroke cerebrovascular remodeling, an important and growing field in neuroscience, by discussing cellular and molecular mechanisms involved, sex differences, limitations of preclinical research design and future directions
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