PDGFR-β restores blood-brain barrier functions in a mouse model of focal cerebral ischemia

Abstract

Although platelet-derived growth factor receptor beta (PDGFR-β) mediates the recruitment of vascular pericytes into ischemic lesion to restore the blood-brain barrier (BBB) dysfunction, its mechanisms still remain elusive . Compared with control PDGFR-β mice (Floxed), postnatally induced systemic PDGFR-β knockout mice (Esr-KO) not only showed severe brain edema, neurologic functional deficits, decreased expression of tight junction (TJ) proteins, abundant endothelial transcytosis, and deformed TJs in the BBB, but also showed reduced expression of transforming growth factor-β (TGF-β) protein after photothrombotic middle cerebral artery occlusion (MCAO). In endothelial-pericyte co-culture, an in vitro model of BBB, the increment in the barrier function of endothelial monolayer induced by pericyte co-culture was completely cancelled by silencing PDGFR-β gene expression in pericytes, and was additively improved by PDGFR-β and TGF-β receptor signals under hypoxia condition. Exogenous PDGF-BB increased the expression of p-Smad2/3, while anti-TGF-β1 antibody at least partially inhibited the phosphorylation of Smad2/3 after PDGF-BB treatment in vitro. Furthermore, pre-administration of TGF-β1 partially alleviated edema formation, neurologic dysfunction, and TJs reduction in Esr-KO mice after MCAO. Accordingly, PDGFR-β signalling, via TGF-β signalling, may be crucial for restoration of BBB integrity after cerebral ischemia and therefore represents a novel potential therapeutic target.

Targeting pericytes for therapeutic approaches to neurological disorders

“…Intracerebroventricular administration of exogenous PDGF-BB has entered human clinical trials and appears to be well-tolerated and safe [ 115 ]. Thus, in a cell culture model, BBB function is better maintained in hypoxia when PDGF-BB or TGFβ is administered [ 132 ]; in status epilepticus, intravenous administration of PDGF-BB reduces blood vessel leakage and normalises blood flow [ 4 ]; and in an animal model of Parkinson’s disease, PDGF-BB may restore neurovascular function by rescuing PDGFRβ signalling [ 111 ].…”

The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

“…198,199 Pericytes increase angiogenesis via the interactions of VEGF and FLT1, 200 Ang1 and Tie2, 201 and PDGFR-β and TGF-β1. 202,203 Several reports exist on the reprogramming of pericytes into neurons (NG2, sox2, and ascl1) 204,205 and other glial (Iba1 + , Glast + ) cells and formation of a glial scar due to the induction of a lineagespecific stem cell marker in ischemic conditions. 206,207 These active pericytes aid in immune suppression, remodeling of PVN, and protection of glioma stem cells (GSC) or glioma-initiating cells (GICs) from ischemic injuries.…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…To what extent these mechanisms are altered in SVD will be an interesting avenue for future research. A link between PDGF and TGFb signaling has recently been presented, where TGFb expression after experimental stroke was reduced in mice with compromised PDGF signaling [146]. PDGF signaling is, as discussed above, a key signaling mechanism in pericytes but there are also other signaling mechanisms important for the BBB and pericytes, including angiopoietin-1/Tie-2 and TGFb signaling [18].…”

“…PDGF signaling is, as discussed above, a key signaling mechanism in pericytes but there are also other signaling mechanisms important for the BBB and pericytes, including angiopoietin-1/Tie-2 and TGFb signaling [18]. A link between PDGF and TGFb signaling has recently been presented, where TGFb expression after experimental stroke was reduced in mice with compromised PDGF signaling [146]. Furthermore, as discussed above, ALK5 signaling in pericytes upregulates TIMP3 expression, leading to enhanced metalloproteinase activity [33].…”