Pericytes of the neurovascular unit: Key functions and signaling pathways

Pericytes (left, pink) – Tumor growth factor-β (TGF-β) secreted by endothelial cells and pericytes binds to TGF-β receptor 2 (TGFβR2) that phosphorylates activin-like kinase 5 (Alk5) (inhibited by Smad7) activating the downstream Smad signaling cascade. Activated Smad2/3 inhibits pericyte proliferation and migration. Recruitment of Smad4 to Smad2/3 complex transcriptionally promotes pericyte differentiation, expression of contractile/extracellular matrix (ECM) proteins, and pericyte attachment. TGF-β also inhibits nitric oxide (NO) generation promoting survival. Activated Notch3 receptor cleaves its Notch intracellular domain (NICD), which promotes survival. Notch-NICD pathway works cooperatively with TGF-β/TGFβR2-Smad-4 pathway to stimulate Rbpj-mediated expression of N-cadherin that increases blood-brain barrier (BBB) stability. Endothelial cells (right, orange) – VEGF-A/VEGFR2 autocrine/paracrine pathway promotes survival via increased expression of anti-apoptotic Bcl-2, Survivin, and X-linked inhibitor of apoptosis protein (XIAP). Vitronectin secreted by pericytes acts on integrin aV on endothelial cells resulting in NFκB-mediated transcriptional expression of VEGF-A and intracrine-mediated VEGF-A/VEGFR2-dependent Bcl-w expression promoting survival. Pericyte-derived Ang1 acts on endothelial Tie2 receptor, and endothelial-secreted Ang2 blocks Ang1 binding to Tie2, acting as a Tie2 antagonist. Ang1/Tie2 activates phosphatidyl inositol 3-phosphate (PI3K)/Akt pathway resulting in inhibition of glycogen synthase kinase 3β (GSK3P), an inhibitor of β-catenin; this leads to β-catenin nuclear translocation resulting in activation of TCF/LEF transcription factors that control expression of several proteins promoting BBB stability (shown in a box). Notch1/4 contributes to β-catenin-mediated BBB stability via the Notch-regulated ankyrin repeat protein (Nrarp), which increases β-catenin nuclear signaling by inhibiting LEF1 degradation and decreases Notch signaling via NICD destabilization. Additionally, Notch1/4-NICD pathway stimulates PDGF-BB expression and RBP-Jκ-mediated expression of N-cadherin contributing to BBB stability. As in pericytes, TGF-β/TGFβR2 pathway in endothelium similarly activates i) Alk5-Smad2/3/4 complex to transcriptionally promote differentiation, inhibit proliferation, and induce RBP-Jκ-mediated expression of N-cadherin, ii) Alk1-Smad1/5/8 to promote proliferation, and iii) Alk1-PI3K/Akt pathway to promote survival and BBB stability. The major facilitator superfamily domain-containing protein 2a (MFSD2A) facilitates luminal-to-abluminal transport of docosahexaenoic acid (DHA), an essential omega-3 fatty acid, and controls formation of the BBB; its expression depends on the presence of pericytes.

Publication

Pericytes of the neurovascular unit: Key functions and signaling pathways. () Melanie D. Sweeney, et al. Nat Neurosci. ;19(6):771-783. Figure: F4. All organisms Bos taurus Mus musculus Felis catus Cavia porcellus Homo sapiens Rattus norvegicus Gallus gallus Danio rerio Drosophila melanogaster Arabidopsis thaliana

Disease mentions