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Fig. 1 | Cell Communication and Signaling

Fig. 1

From: Targeting pericytes for neurovascular regeneration

Fig. 1

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 disease, and Parkinson’s disease weaken BBB integrity through activating pericytes. By thrombin elevation in CNS diseases, PAR1 activation results in MMP-9 secretion and subsequent ECM degradation through downstream PKCδ-ERK1/2 and PKCθ-Akt signaling pathways. In addition, there are other mechanisms for MMP-9 release and ECM degradation after ischemic stroke related to increased TNF-α content and up-regulation MMP-9 inside pericytes through MAPK and PI3K/Akt signaling pathways. VEGF production inside pericytes happens and subsequent BBB disruption occurs through decreasing claudin 5 expression. In spite of these disruptive mechanisms of pericytes in response to ischemic stroke, pericytes behavior complexity stigmatizes its role by exerting CNS homeostasis, neuroprotective and angiogenic activity after ischemic stroke. The hypoxia-induced FGFR1 up-regulation and tissue acidification promotes bFGF autocrine signaling inside pericytes following ischemic stroke which intensifies PDGFRB up-regulation. PDGFRB signaling activation supports CNS homeostasis, neuroprotection, and angiogenesis through releasing growth factors microvesicles and generating fibrotic scar. TSP1 reinforces PDGFRB signaling aiming to pericytes proliferation and migration

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