The role of transforming growth factor- in hypertension-induced cerebrovascular remodeling

Background: Hypertension (HT) promotes structural and functional changes in the cerebral microcirculation that can provoke irreversible cerebrovascular injury, leading to neuronal loss brain atrophy,1 cognitive impairment, vascular dementia,2 Alzheimer’s disease.3 Currently, mechanisms consequences of such remodeling are not fully understood. Transforming growth factor (TGF) is a morphogen regulates cellular differentiation, induces endothelial-to-mesenchymal transition (EndoMT), works as contractile-to-synthetic switch smooth muscle cells (VSMC) phenotype.4 Plasma levels TGF increased HT patients, spontaneously hypertensive rats (SHR) exhibit fibrosis.5 Although coincidental, causal roles through which elevated may drive suspected, but unproven. We hypothesize HT-induced drives remodeling, decreases blood-brain barrier impairs autoregulation.
 Methods: Brain cortices penetrating microvessels (BMVs) were isolated from male female SHR Wistar-Kyoto (WKY, control), subjected western blotting immunofluorescence labeling for endothelial cell (EC) VSMC differentiation markers, canonical pathway markers SMAD2, 3 4, well basement membrane protein expression, glial fibrillary acidic (GFAP) marker astrocyte inflammation. Additionally, TGF-treated rat retinal microvascular (RRMECs), human (hCMEC/D3) ± inhibitor vactosertib, also assess expression.
 Results: was significantly BMVs. Moreover, GFAP cortex. The EC junctional proteins platelet adhesion molecule-1 (PECAM-1) endothelial-cadherin (VE-cadherin), decreased SHR. In contrast, CRBP-1, synthetic VSMC, collagen IV fibronectin Interestingly, had SMAD2/3, evident SHRs, indicating possible role non-canonical SHRs. -smooth actin (-SMA) VE-cadherin expression RRMECs D3 cells, consistent with EndoMT. inhibition vactosertib reversed these effects suppressed -SMA, maintained VE-Cadherin similar control D3s.
 Conclusions: now have strong evidence where mediates both differentiated phenotypes. reversal using blockers suggests therapy modulate represent means remodeling.