Targeting pericytes for neurovascular regeneration

Pericytes contribute in homeostasis of the BBB through different mechanisms. TGF-β signaling inside pericytes supports the BBB integrity by enhancing fibronectin production, basal membrane formation and stimulating tight junctions expression. TGF-β signaling also participates in capillary-like structures formation. Along with TGF-β signaling, pericytes derived Ang-1 enhances occludin up-regulation inside ECs which stabilize BBB integrity. Mutually, ECs support adjacent pericytes by improving pericyte-EC integration by up-regulating N-cadherin and the prevention of pericytes migration. Two mechanisms have been suggested for ECs supporting role. First, TGF-β and BMP signaling pathways play enhancing role on N-cadherin up-regulation inside ECs through Smad4. The second mechanism is related to the stimulatory effect of VEGF in the expression of DLL4 inside ECs and attaching to receptor Notch3 on pericytes surface, triggering Notch signaling, N-cadherin up-regulation inside pericytes. Various mechanisms have been identified for the induction of pericytes proliferation and migration. During hyperglycemia or hypoxia, an elevated Ang-2 level activates cognate receptor Tie-2 which induces pericytes migratory activity by detaching cells from the ECM. The inductive mechanism for Ang-2 elevation in hypoxia occurs via pericytes HIF-1α and subsequent VEGF signaling. Also, the promotion of HIF-1α, VEGF, and Nox4 signaling after hypoxia enhances pericytes proliferative activity. In response to hypoxia, pericytes support neuronal survival with astrocytes collaboration. After hypoxia, pericytes NT-3 releasing activates astrocytes TrkC receptors in which upregulates NGF through ERK1/2 signaling pathway. Pericytes plays a major role in diabetic pathology and other hyperglycemic conditions. In these circumstances, pericytes respond to accumulated AGEs through various mechanisms. ANG-2-related activation of ANG type 1 receptor inside retina and AGEs stimulated TGF-β autocrine signaling inside pericytes, leading to basal membrane hypertrophy through increased production of fibronectin. The postulated mechanism for diabetic retinopathy via AGEs receptors occurs by activating downstream Src-Erk1/2-FAK-1-Paxillin signaling pathway which leads to diabetic retinopathy and pericytes migration. Also, HIV and ANG-2 cause pericytes migration and diabetic retinopathy through PDGF-BB autocrine signaling. Inside ECs claudin 5 down-regulation via VEGF and MMP-2 elevation leads to BBB disruption. Different types of CNS diseases such as ischemic stroke, intracerebral hemorrhage, Alzheimer’s