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Pericytes Regulate Cerebral Perfusion through VEGFR1 in Ischemic Stroke

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Abstract

Neurons in the penumbra (the area surrounding ischemic tissue that consists of still viable tissue but with reduced blood flow and oxygen transport) may be rescued following stroke if adequate perfusion is restored in time. It has been speculated that post-stroke angiogenesis in the penumbra can reduce damage caused by ischemia. However, the mechanism for neovasculature formation in the brain remains unclear and vascular-targeted therapies for brain ischemia remain suboptimal. Here, we show that VEGFR1 was highly upregulated in pericytes after stroke. Knockdown of VEGFR1 in pericytes led to increased infarct area and compromised post-ischemia vessel formation. Furthermore, in vitro studies confirmed a critical role for pericyte-derived VEGFR1 in both endothelial tube formation and pericyte migration. Interestingly, our results show that pericyte-derived VEGFR1 has opposite effects on Akt activity in endothelial cells and pericytes. Collectively, these results indicate that pericyte-specific expression of VEGFR1 modulates ischemia-induced vessel formation and vascular integrity in the brain.

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References

  • Al Ahmad A, Taboada CB, Gassmann M, Ogunshola OO (2011) Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult. J Cereb Blood Flow Metab 31(2):693–705

    Article  PubMed  Google Scholar 

  • Arenillas JF, Sobrino T, Castillo J, Davalos A (2007) The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med 9(3):205–212

    Article  PubMed  Google Scholar 

  • Blanco R, Gerhardt H (2013) VEGF and Notch in tip and stalk cell selection. Cold Spring Harb Perspect Med 3(1):a006569

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boucher JM, Clark RP, Chong DC, Citrin KM, Wylie LA, Bautch VL (2017) Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis. Nat Commun 8:15699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dzietko M, Derugin N, Wendland MF, Vexler ZS, Ferriero DM (2013) Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Transl Stroke Res 4(2):189–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eilken HM, Dieguez-Hurtado R, Schmidt I, Nakayama M, Jeong HW, Arf H, Adams S, Ferrara N, Adams RH (2017) Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1. Nat Commun 8(1):1574

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • ElAli A, Theriault P, Rivest S (2014) The role of pericytes in neurovascular unit remodeling in brain disorders. Int J Mol Sci 15(4):6453–6474

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ergul A, Alhusban A, Fagan SC (2012) Angiogenesis: a harmonized target for recovery after stroke. Stroke 43(8):2270–2274

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    Article  CAS  PubMed  Google Scholar 

  • Filosa JA, Morrison HW, Iddings JA, Du W, Kim KJ (2016) Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. Neuroscience 323:96–109

    Article  CAS  PubMed  Google Scholar 

  • Font MA, Arboix A, Krupinski J (2010) Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev 6(3):238–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fuxe J, Tabruyn S, Colton K, Zaid H, Adams A, Baluk P, Lashnits E, Morisada T, Le T, O’Brien S, Epstein DM, Koh GY, McDonald DM (2011) Pericyte requirement for anti-leak action of angiopoietin-1 and vascular remodeling in sustained inflammation. Am J Pathol 178(6):2897–2909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geiseler SJ, Morland C (2018) The janus face of VEGF in stroke. Int J Mol Sci 19(5):1362

    Article  PubMed Central  CAS  Google Scholar 

  • Greenberg DA, Jin K (2013) Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol Life Sci 70(10):1753–1761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hellberg C, Ostman A, Heldin CH (2010) PDGF and vessel maturation. Recent Results Cancer Res 180:103–114

    Article  CAS  PubMed  Google Scholar 

  • Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126(14):3047–3055

    Article  CAS  PubMed  Google Scholar 

  • Herbert SP, Stainier DY (2011) Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat Rev Mol Cell Biol 12(9):551–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iadecola C, Anrather J (2011) Stroke research at a crossroad: asking the brain for directions. Nat Neurosci 14(11):1363–1368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imoukhuede PI, Dokum AO, Annex BH, Popel AS (2013) Endothelial cell-by-cell profiling reveals the temporal dynamics of VEGFR1 and VEGFR2 membrane localization after murine hindlimb ischemia. Am J Physiol Heart and Circ Physiol 304(8):H1085–H1093

    Article  CAS  Google Scholar 

  • Karar J, Maity A (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 4:51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kerr BA, West XZ, Kim YW, Zhao Y, Tischenko M, Cull RM, Phares TW, Peng XD, Bernier-Latmani J, Petrova TV, Adams RH, Hay N, Naga Prasad SV, Byzova TV (2016) Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium. Nat Commun 7:10960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krupinski J, Issa R, Bujny T, Slevin M, Kumar P, Kumar S, Kaluza J (1997) A putative role for platelet-derived growth factor in angiogenesis and neuroprotection after ischemic stroke in humans. Stroke 28(3):564–573

    Article  CAS  PubMed  Google Scholar 

  • Lamalice L, Le Boeuf F, Huot J (2007) Endothelial cell migration during angiogenesis. Circ Res 100(6):782–794

    Article  CAS  PubMed  Google Scholar 

  • Lee HK, Chauhan SK, Kay E, Dana R (2011) Flt-1 regulates vascular endothelial cell migration via a protein tyrosine kinase-7-dependent pathway. Blood 117(21):5762–5771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liman TG, Endres M (2012) New vessels after stroke: postischemic neovascularization and regeneration. Cerebrovasc Dis 33(5):492–499

    Article  CAS  PubMed  Google Scholar 

  • Mae M, Armulik A, Betsholtz C (2011) Getting to know the cast - cellular interactions and signaling at the neurovascular unit. Curr Pharm Des 17(26):2750–2754

    Article  CAS  PubMed  Google Scholar 

  • Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67(2):181–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moya IM, Umans L, Maas E, Pereira PN, Beets K, Francis A, Sents W, Robertson EJ, Mummery CL, Huylebroeck D, Zwijsen A (2012) Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades. Dev Cell 22(3):501–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paredes I, Himmels P, Ruiz de Almodovar C (2018) Neurovascular communication during CNS development. Dev Cell 45(1):10–32

    Article  CAS  PubMed  Google Scholar 

  • Ribatti D, Nico B, Crivellato E (2011) The role of pericytes in angiogenesis. Int J Dev Biol 55(3):261–268

    Article  CAS  PubMed  Google Scholar 

  • Robciuc MR, Kivela R, Williams IM, de Boer JF, van Dijk TH, Elamaa H, Tigistu-Sahle F, Molotkov D, Leppanen VM, Kakela R, Eklund L, Wasserman DH, Groen AK, Alitalo K (2016) VEGFB/VEGFR1-induced expansion of adipose vasculature counteracts obesity and related metabolic complications. Cell Metab 23(4):712–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibuya M (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 153(1):13–19

    Article  CAS  PubMed  Google Scholar 

  • Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312(5):549–560

    Article  CAS  PubMed  Google Scholar 

  • Simons M, Gordon E, Claesson-Welsh L (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17(10):611–625

    Article  CAS  PubMed  Google Scholar 

  • Stankowski JN, Gupta R (2011) Therapeutic targets for neuroprotection in acute ischemic stroke: lost in translation? Antioxid Redox Signal 14(10):1841–1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sweeney MD, Ayyadurai S, Zlokovic BV (2016) Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 19(6):771–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ucuzian AA, Gassman AA, East AT, Greisler HP (2010) Molecular mediators of angiogenesis. J Burn Care Res 31(1):158–175

    Article  PubMed  Google Scholar 

  • Vanhollebeke B, Stone OA, Bostaille N, Cho C, Zhou Y, Maquet E, Gauquier A, Cabochette P, Fukuhara S, Mochizuki N, Nathans J, Stainier DY (2015) Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/beta-catenin pathway during brain angiogenesis. Elife. https://doi.org/10.7554/eLife.06489

    Article  PubMed  PubMed Central  Google Scholar 

  • Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14(11):1398–1405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV (2011) Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener 6(1):11

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV (2015) Establishment and dysfunction of the blood-brain barrier. Cell 163(5):1064–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Fund for Distinguished Young Scholars (81525008) and the National Natural Science Fund for Outstanding Young Scholars (81822015).

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Contributions

C.X.G., Q.Z, F.F.L., and Q.W.Y. conceived this study and designed the experiments. C.X.G. established the pMCAO models. C.X.G., Q.Z., X.Y.X., J.J.Y., G.Q.Y, and H.J.C. performed the experiments and analyzed the data. J.L., C.M.D., R.X., and Z.M.Q. performed immunofluorescence analysis. Z.Y.M., K.Z., and F.X.W. gave scientific advice. C.X.G, Q.Z., F.F.L, and Q.W.Y. wrote the paper.

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Correspondence to Fangfei Li or Qing-Wu Yang.

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Gong, CX., Zhang, Q., Xiong, XY. et al. Pericytes Regulate Cerebral Perfusion through VEGFR1 in Ischemic Stroke. Cell Mol Neurobiol 42, 1897–1908 (2022). https://doi.org/10.1007/s10571-021-01071-w

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  • DOI: https://doi.org/10.1007/s10571-021-01071-w

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