TABLE 1.

Major features (non-exhaustive list) of structural and functional remodeling of the neurovascular unit following stroke.

		Selected references
Structural NVU Remodeling
Ischemic Stroke	– Reparative angiogenesis primarily in the peri-infarct. – Biphasic BBB breakdown: (1) Increased caveolae-mediated transcytosis. (2) Tight junction breakdown. – Secretion of MMPs by pericytes, ECs, and microglia promotes degradation of the basement membrane and TJ disruption, leading, to increased BBB permeability and edema. – Secreted MMPs also 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 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.	Chow et al., 2001; Hangai et al., 2002; Beck et al., 2008; Krum et al., 2008; Yu et al., 2010; Yenari et al., 2010; Jiao et al., 2011; Ben-Zvi et al., 2014; ElAli et al., 2014; Knowland et al., 2014; Jolivel et al., 2015; Choi et al., 2016; Nahirney et al., 2016; Thomsen et al., 2017; Underly et al., 2017; Eldahshan et al., 2019; Howe et al., 2019; Munji et al., 2019; Yao, 2019; Shibahara et al., 2020.
Hemorrhagic stroke	– ECs proliferate around hematoma following 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. – VEGF can also increase BBB permeability, which may help peripheral macrophages infiltrate into the brain.	Manoonkitiwongsa et al., 2001; Gould et al., 2006; Chen et al., 2013; Fu et al., 2014; Lan et al., 2017; Zhang et al., 2017; Gautam et al., 2020; Mechtouff et al., 2020.
Functional NVU Remodeling
Ischemic stroke	– Acute loss of CBF initiates vascular remodeling via eNOS. – Acute hypoxia induces pericyte relaxation, however, sustained hypoxia leads to pericyte constriction and death. – Functional changes in astrocytes significantly affect NVC. – Decrease in glutathione impairs astrocytic regulation of CBF. – Astrocytes implicated in propagating CSD and VSMC constriction contributing to decreased CBF. – Cell death of perivascular neurons exacerbates brain damage and leads to neurovascular uncoupling. – Hypoxia activates and stabilizes HIFs, upregulating VEGF signaling and promoting angiogenesis. – Angiogenic response provides a scaffold for neuronal regeneration, mediated by neural precursor cells.	Marti et al., 2000; Attwell et al., 2010; Arimura et al., 2012; Fernandez-Klett et al., 2013; Hall et al., 2014; O’Donnell, 2014; Hoffmann et al., 2015; Reeson et al., 2015; Howarth et al., 2017; Cai et al., 2018; Rovegno and Saez, 2018; McConnell et al., 2019; Tornabene et al., 2019.
Hemorrhagic stroke	– VEGF and its receptors upregulated persistently. – Increased VEGF increases vessel density and improves stroke outcome. – Beneficial effects of VEGF mediated through aquaporin-4. – Morphology of newly formed vessels resemble that of the developing brain.	Josko, 2003; Tang et al., 2007; Chu et al., 2013; Sugimoto and Chung, 2020.

Selected references are displayed. BBB, blood–brain barrier; TJ: tight junction; MMPs, matrix metalloproteinases; EC, endothelial cell; ICH, intracerebral hemorrhage; NVC, neurovascular coupling; NVU, neurovascular unit; CBF, cerebral blood flow; CSD, cortical spreading depression; VSMC, vascular smooth muscle cell; HIF, hypoxia-inducible transcription factors; VEGF, vascular endothelial growth factor.