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01-02-2019 | Original Paper

Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation

Authors: Jordan Darden, Laura Beth Payne, Huaning Zhao, John C. Chappell

Published in: Angiogenesis | Issue 1/2019

Abstract

Pericyte investment into new blood vessels is essential for vascular development such that mis-regulation within this phase of vessel formation can contribute to numerous pathologies including arteriovenous and cerebrovascular malformations. It is critical therefore to illuminate how angiogenic signaling pathways intersect to regulate pericyte migration and investment. Here, we disrupted vascular endothelial growth factor-A (VEGF-A) signaling in ex vivo and in vitro models of sprouting angiogenesis, and found pericyte coverage to be compromised during VEGF-A perturbations. Pericytes had little to no expression of VEGF receptors, suggesting VEGF-A signaling defects affect endothelial cells directly but pericytes indirectly. Live imaging of ex vivo angiogenesis in mouse embryonic skin revealed limited pericyte migration during exposure to exogenous VEGF-A. During VEGF-A gain-of-function conditions, pericytes and endothelial cells displayed abnormal transcriptional changes within the platelet-derived growth factor-B (PDGF-B) and Notch pathways. To further test potential crosstalk between these pathways in pericytes, we stimulated embryonic pericytes with Notch ligands Delta-like 4 (Dll4) and Jagged-1 (Jag1) and found induction of Notch pathway activity but no changes in PDGF Receptor-β (Pdgfrβ) expression. In contrast, PDGFRβ protein levels decreased with mis-regulated VEGF-A activity, observed in the effects on full-length PDGFRβ and a truncated PDGFRβ isoform generated by proteolytic cleavage or potentially by mRNA splicing. Overall, these observations support a model in which, during the initial stages of vascular development, pericyte distribution and coverage are indirectly affected by endothelial cell VEGF-A signaling and the downstream regulation of PDGF-B-PDGFRβ dynamics, without substantial involvement of pericyte Notch signaling during these early stages.

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Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2017) Heart disease and stroke statistics-2017 update: a report from the American heart association. Circulation 135(10):e146–e603. https://doi.org/10.1161/CIR.0000000000000485 CrossRefPubMedPubMedCentral

Whitehead KJ, Smith MC, Li DY (2013) Arteriovenous malformations and other vascular malformation syndromes. Cold Spring Harb Perspect Med 3(2):a006635. https://doi.org/10.1101/cshperspect.a006635 CrossRefPubMedPubMedCentral

Leblanc GG, Golanov E, Awad IA, Young WL, Biology of Vascular Malformations of the Brain NWC (2009) Biology of vascular malformations of the brain. Stroke 40(12):e694–e702. https://doi.org/10.1161/STROKEAHA.109.563692 CrossRefPubMedPubMedCentral

Kofler NM, Cuervo H, Uh MK, Murtomaki A, Kitajewski J (2015) Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations. Sci Rep 5:16449. https://doi.org/10.1038/srep16449 CrossRefPubMedPubMedCentral

Dave JM, Mirabella T, Weatherbee SD, Greif DM (2018) Pericyte ALK5/TIMP3 axis contributes to endothelial morphogenesis in the developing brain. Dev Cell. https://doi.org/10.1016/j.devcel.2018.01.018 CrossRefPubMedPubMedCentral

Chappell JC, Bautch VL (2010) Vascular development: genetic mechanisms and links to vascular disease. Curr Top Dev Biol 90:43–72. https://doi.org/10.1016/S0070-2153(10)90002-1 CrossRefPubMed

Vieira JM, Ruhrberg C, Schwarz Q (2010) VEGF receptor signaling in vertebrate development. Organogenesis 6(2):97–106CrossRefPubMedPubMedCentral

Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161(6):1163–1177CrossRefPubMedPubMedCentral

Kappas NC, Zeng G, Chappell JC, Kearney JB, Hazarika S, Kallianos KG, Patterson C, Annex BH, Bautch VL (2008) The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. J Cell Biol 181(5):847–858. https://doi.org/10.1083/jcb.200709114 CrossRefPubMedPubMedCentral

10.

Strilic B, Kucera T, Eglinger J, Hughes MR, McNagny KM, Tsukita S, Dejana E, Ferrara N, Lammert E (2009) The molecular basis of vascular lumen formation in the developing mouse aorta. Dev Cell 17(4):505–515. https://doi.org/10.1016/j.devcel.2009.08.011 CrossRefPubMed

11.

Chappell JC, Mouillesseaux KP, Bautch VL (2013) Flt-1 (vascular endothelial growth factor receptor-1) is essential for the vascular endothelial growth factor-notch feedback loop during angiogenesis. Arterioscler Thromb Vasc Biol 33(8):1952–1959. https://doi.org/10.1161/ATVBAHA.113.301805 CrossRefPubMedPubMedCentral

12.

Jakobsson L, Bentley K, Gerhardt H (2009) VEGFRs and Notch: a dynamic collaboration in vascular patterning. Biochem Soc Trans 37(Pt 6):1233–1236. https://doi.org/10.1042/BST0371233 CrossRefPubMed

13.

Siekmann AF, Covassin L, Lawson ND (2008) Modulation of VEGF signalling output by the Notch pathway. Bioessays 30(4):303–313. https://doi.org/10.1002/bies.20736 CrossRefPubMed

14.

Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445(7129):776–780. https://doi.org/10.1038/nature05571 CrossRefPubMed

15.

Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314(1):15–23. https://doi.org/10.1007/s00441-003-0745-x CrossRefPubMed

16.

Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, Backstrom G, Fredriksson S, Landegren U, Nystrom HC, Bergstrom G, Dejana E, Ostman A, Lindahl P, Betsholtz C (2003) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17(15):1835–1840. https://doi.org/10.1101/gad.266803 CrossRefPubMedPubMedCentral

17.

Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood-brain barrier. Nature 468(7323):557–561. https://doi.org/10.1038/nature09522 CrossRefPubMed

18.

Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468(7323):562–566. https://doi.org/10.1038/nature09513 CrossRefPubMedPubMedCentral

19.

Stratman AN, Pezoa SA, Farrelly OM, Castranova D, Dye LE III, Butler MG, Sidik H, Talbot WS, Weinstein BM (2017) Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta. Development 144(1):115–127. https://doi.org/10.1242/dev.143131 CrossRefPubMedPubMedCentral

20.

Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J (2015) Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87(1):95–110. https://doi.org/10.1016/j.neuron.2015.06.001 CrossRefPubMedPubMedCentral

21.

Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O’Farrell FM, Buchan AM, Lauritzen M, Attwell D (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508(7494):55–60. https://doi.org/10.1038/nature13165 CrossRefPubMedPubMedCentral

22.

Fernandez-Klett F, Potas JR, Hilpert D, Blazej K, Radke J, Huck J, Engel O, Stenzel W, Genove G, Priller J (2013) Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J Cereb Blood Flow Metab 33(3):428–439. https://doi.org/10.1038/jcbfm.2012.187 CrossRefPubMed

23.

Hamilton NB, Attwell D, Hall CN (2010) Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenerg. https://doi.org/10.3389/fnene.2010.00005 CrossRef

24.

Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro-oncology 7(4):452–464. https://doi.org/10.1215/S1152851705000232 CrossRefPubMedPubMedCentral

25.

Kofler NM, Shawber CJ, Kangsamaksin T, Reed HO, Galatioto J, Kitajewski J (2011) Notch signaling in developmental and tumor angiogenesis. Genes Cancer 2(12):1106–1116. https://doi.org/10.1177/1947601911423030 CrossRefPubMedPubMedCentral

26.

Schrimpf C, Teebken OE, Wilhelmi M, Duffield JS (2014) The role of pericyte detachment in vascular rarefaction. J Vasc Res 51(4):247–258. https://doi.org/10.1159/000365149 CrossRefPubMed

27.

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. https://doi.org/10.1038/s41467-017-01738-3 CrossRefPubMedPubMedCentral

28.

Cao R, Xue Y, Hedlund EM, Zhong Z, Tritsaris K, Tondelli B, Lucchini F, Zhu Z, Dissing S, Cao Y (2010) VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. Proc Natl Acad Sci USA 107(2):856–861. https://doi.org/10.1073/pnas.0911661107 CrossRefPubMed

29.

He L, Vanlandewijck M, Raschperger E, Andaloussi Mae M, Jung B, Lebouvier T, Ando K, Hofmann J, Keller A, Betsholtz C (2016) Analysis of the brain mural cell transcriptome. Sci Rep 6:35108. https://doi.org/10.1038/srep35108 CrossRefPubMedPubMedCentral

30.

Fruttiger M (2002) Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Invest Ophthalmol Vis Sci 43(2):522–527PubMed

31.

Shih SC, Ju M, Liu N, Smith LE (2003) Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 112(1):50–57CrossRefPubMedPubMedCentral

32.

Matsumoto K, Azami T, Otsu A, Takase H, Ishitobi H, Tanaka J, Miwa Y, Takahashi S, Ema M (2012) Study of normal and pathological blood vessel morphogenesis in Flt1-tdsRed BAC Tg mice. Genesis 50(7):561–571. https://doi.org/10.1002/dvg.22031 CrossRefPubMed

33.

Luo L, Uehara H, Zhang X, Das SK, Olsen T, Holt D, Simonis JM, Jackman K, Singh N, Miya TR, Huang W, Ahmed F, Bastos-Carvalho A, Le YZ, Mamalis C, Chiodo VA, Hauswirth WW, Baffi J, Lacal PM, Orecchia A, Ferrara N, Gao G, Young-Hee K, Fu Y, Owen L, Albuquerque R, Baehr W, Thomas K, Li DY, Chalam KV, Shibuya M, Grisanti S, Wilson DJ, Ambati J, Ambati BK (2013) Photoreceptor avascular privilege is shielded by soluble VEGF receptor-1. Elife 2:e00324. https://doi.org/10.7554/eLife.00324 CrossRefPubMedPubMedCentral

34.

Liu H, Kennard S, Lilly B (2009) NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res 104(4):466–475. https://doi.org/10.1161/CIRCRESAHA.108.184846 CrossRefPubMedPubMedCentral

35.

Henshall TL, Keller A, He L, Johansson BR, Wallgard E, Raschperger E, Mae MA, Jin S, Betsholtz C, Lendahl U (2015) Notch3 is necessary for blood vessel integrity in the central nervous system. Arterioscler Thromb Vasc Biol 35(2):409–420. https://doi.org/10.1161/ATVBAHA.114.304849 CrossRefPubMed

36.

Pedrosa AR, Trindade A, Carvalho C, Graca J, Carvalho S, Peleteiro MC, Adams RH, Duarte A (2015) Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions. Oncotarget 6(27):24404–24423. https://doi.org/10.18632/oncotarget.4380 CrossRefPubMedPubMedCentral

37.

Volz KS, Jacobs AH, Chen HI, Poduri A, McKay AS, Riordan DP, Kofler N, Kitajewski J, Weissman I, Red-Horse K (2015) Pericytes are progenitors for coronary artery smooth muscle. Elife. https://doi.org/10.7554/eLife.10036 CrossRefPubMedPubMedCentral

38.

Jin S, Hansson EM, Tikka S, Lanner F, Sahlgren C, Farnebo F, Baumann M, Kalimo H, Lendahl U (2008) Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ Res 102(12):1483–1491. https://doi.org/10.1161/CIRCRESAHA.107.167965 CrossRefPubMed

39.

Wang Y, Pan L, Moens CB, Appel B (2014) Notch3 establishes brain vascular integrity by regulating pericyte number. Development 141(2):307–317. https://doi.org/10.1242/dev.096107 CrossRefPubMedPubMedCentral

40.

Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, Aiello LP, Kern TS, King GL (2009) Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med 15(11):1298–1306. https://doi.org/10.1038/nm.2052 CrossRefPubMedPubMedCentral

41.

Abramsson A, Kurup S, Busse M, Yamada S, Lindblom P, Schallmeiner E, Stenzel D, Sauvaget D, Ledin J, Ringvall M, Landegren U, Kjellen L, Bondjers G, Li JP, Lindahl U, Spillmann D, Betsholtz C, Gerhardt H (2007) Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev 21(3):316–331. https://doi.org/10.1101/gad.398207 CrossRefPubMedPubMedCentral

42.

Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153(3):543–553CrossRefPubMedPubMedCentral

43.

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):3047–3055PubMed

44.

Sagare AP, Sweeney MD, Makshanoff J, Zlokovic BV (2015) Shedding of soluble platelet-derived growth factor receptor-beta from human brain pericytes. Neurosci Lett 607:97–101. https://doi.org/10.1016/j.neulet.2015.09.025 CrossRefPubMedPubMedCentral

45.

Hutter-Schmid B, Humpel C (2016) Platelet-derived growth factor receptor-beta is differentially regulated in primary mouse pericytes and brain slices. Curr Neurovasc Res 13(2):127–134CrossRefPubMed

46.

Mendelson K, Swendeman S, Saftig P, Blobel CP (2010) Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways. J Biol Chem 285(32):25024–25032. https://doi.org/10.1074/jbc.M110.102566 CrossRefPubMedPubMedCentral

47.

Duan DS, Pazin MJ, Fretto LJ, Williams LT (1991) A functional soluble extracellular region of the platelet-derived growth factor (PDGF) beta-receptor antagonizes PDGF-stimulated responses. J Biol Chem 266(1):413–418PubMed

48.

Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 95(16):9349–9354CrossRefPubMedPubMedCentral

49.

Sawano A, Takahashi T, Yamaguchi S, Aonuma M, Shibuya M (1996) Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell Growth Differ 7(2):213–221PubMed

50.

Chappell JC, Cluceru JG, Nesmith JE, Mouillesseaux KP, Bradley V, Hartland C, Hashambhoy-Ramsay YL, Walpole J, Peirce SM, Gabhann FM, Bautch VL (2016) Flt-1 (VEGFR-1) coordinates discrete stages of blood vessel formation. Cardiovasc Res 111(1):84–93. https://doi.org/10.1093/cvr/cvw091 CrossRefPubMedPubMedCentral

51.

Roberts DM, Kearney JB, Johnson JH, Rosenberg MP, Kumar R, Bautch VL (2004) The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. Am J Pathol 164(5):1531–1535CrossRefPubMedPubMedCentral

52.

Taylor SM, Nevis KR, Park HL, Rogers GC, Rogers SL, Cook JG, Bautch VL (2010) Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels. Blood 116(16):3108–3117. https://doi.org/10.1182/blood-2010-01-266197 CrossRefPubMedPubMedCentral

53.

Zeng G, Taylor SM, McColm JR, Kappas NC, Kearney JB, Williams LH, Hartnett ME, Bautch VL (2007) Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation. Blood 109(4):1345–1352CrossRefPubMedPubMedCentral

54.

Ho VC, Duan LJ, Cronin C, Liang BT, Fong GH (2012) Elevated vascular endothelial growth factor receptor-2 abundance contributes to increased angiogenesis in vascular endothelial growth factor receptor-1-deficient mice. Circulation 126(6):741–752. https://doi.org/10.1161/CIRCULATIONAHA.112.091603 CrossRefPubMedPubMedCentral

55.

Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, Yang X, Jensen L, Lim S, Feng N, Xue Y, Li X, Larsson O, Ohhashi T, Cao Y (2013) Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis. Nat Commun 4:2129. https://doi.org/10.1038/ncomms3129 CrossRefPubMed

56.

Kearney JB, Bautch VL (2003) In vitro differentiation of mouse ES cells: hematopoietic and vascular development. Methods Enzymol 365:83–98CrossRefPubMed

57.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9(7):676–682. https://doi.org/10.1038/nmeth.2019 CrossRefPubMed

58.

Stegmuller J, Schneider S, Hellwig A, Garwood J, Trotter J (2002) AN2, the mouse homologue of NG2, is a surface antigen on glial precursor cells implicated in control of cell migration. J Neurocytol 31(6–7):497–505CrossRefPubMed

59.

Zhao H, Darden J, Chappell JC (2018) Establishment and characterization of an embryonic pericyte cell line. Microcirculation. https://doi.org/10.1111/micc.12461 CrossRefPubMedPubMedCentral

60.

Nesmith JE, Chappell JC, Cluceru JG, Bautch VL (2017) Blood vessel anastomosis is spatially regulated by Flt1 during angiogenesis. Development 144(5):889–896. https://doi.org/10.1242/dev.145672 CrossRefPubMedPubMedCentral

61.

Chappell JC, Taylor SM, Ferrara N, Bautch VL (2009) Local guidance of emerging vessel sprouts requires soluble Flt-1. Dev Cell 17(3):377–386. https://doi.org/10.1016/j.devcel.2009.07.011 CrossRefPubMedPubMedCentral

62.

Wild R, Klems A, Takamiya M, Hayashi Y, Strahle U, Ando K, Mochizuki N, van Impel A, Schulte-Merker S, Krueger J, Preau L, le Noble F (2017) Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization. Nat Commun 8:13991. https://doi.org/10.1038/ncomms13991 CrossRefPubMedPubMedCentral

63.

Krueger J, Liu D, Scholz K, Zimmer A, Shi Y, Klein C, Siekmann A, Schulte-Merker S, Cudmore M, Ahmed A, le Noble F (2011) Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo. Development 138(10):2111–2120. https://doi.org/10.1242/dev.063933 CrossRefPubMedPubMedCentral

64.

Zygmunt T, Gay CM, Blondelle J, Singh MK, Flaherty KM, Means PC, Herwig L, Krudewig A, Belting HG, Affolter M, Epstein JA, Torres-Vazquez J (2011) Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1. Dev Cell 21(2):301–314. https://doi.org/10.1016/j.devcel.2011.06.033 CrossRefPubMedPubMedCentral

65.

Stefater JA III, Lewkowich I, Rao S, Mariggi G, Carpenter AC, Burr AR, Fan J, Ajima R, Molkentin JD, Williams BO, Wills-Karp M, Pollard JW, Yamaguchi T, Ferrara N, Gerhardt H, Lang RA (2011) Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature 474(7352):511–515. https://doi.org/10.1038/nature10085 CrossRefPubMedPubMedCentral

66.

Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456(7223):809–813. https://doi.org/10.1038/nature07424 CrossRefPubMedPubMedCentral

67.

Yamagishi S, Yonekura H, Yamamoto Y, Fujimori H, Sakurai S, Tanaka N, Yamamoto H (1999) Vascular endothelial growth factor acts as a pericyte mitogen under hypoxic conditions. Lab Invest 79(4):501–509PubMed

68.

Hagedorn M, Balke M, Schmidt A, Bloch W, Kurz H, Javerzat S, Rousseau B, Wilting J, Bikfalvi A (2004) VEGF coordinates interaction of pericytes and endothelial cells during vasculogenesis and experimental angiogenesis. Dev Dyn 230(1):23–33. https://doi.org/10.1002/dvdy.20020 CrossRefPubMed

69.

Larina IV, Shen W, Kelly OG, Hadjantonakis AK, Baron MH, Dickinson ME (2009) A membrane associated mCherry fluorescent reporter line for studying vascular remodeling and cardiac function during murine embryonic development. Anat Rec 292(3):333–341. https://doi.org/10.1002/ar.20821 CrossRef

70.

Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215. https://doi.org/10.1016/j.devcel.2011.07.001 CrossRefPubMed

71.

Trotter J, Karram K, Nishiyama A (2010) NG2 cells: properties, progeny and origin. Brain Res Rev 63(1–2):72–82. https://doi.org/10.1016/j.brainresrev.2009.12.006 CrossRefPubMedPubMedCentral

72.

Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T (2016) What is a pericyte? J Cereb Blood Flow Metab 36(2):451–455. https://doi.org/10.1177/0271678X15610340 CrossRefPubMed

73.

Berthiaume AA, Grant RI, McDowell KP, Underly RG, Hartmann DA, Levy M, Bhat NR, Shih AY (2018) Dynamic remodeling of pericytes in vivo maintains capillary coverage in the adult mouse brain. Cell Rep 22(1):8–16. https://doi.org/10.1016/j.celrep.2017.12.016 CrossRefPubMedPubMedCentral

74.

Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8(12):942–956. https://doi.org/10.1038/nrc2524 CrossRefPubMed

75.

Arreola A, Payne LB, Julian MH, de Cubas AA, Daniels AB, Taylor S, Zhao H, Darden J, Bautch VL, Rathmell WK, Chappell JC (2018) Von Hippel-Lindau mutations disrupt vascular patterning and maturation via Notch. JCI Insight. https://doi.org/10.1172/jci.insight.92193 CrossRefPubMedPubMedCentral

76.

Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376(6535):66–70CrossRefPubMed

77.

Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97(6):512–523. https://doi.org/10.1161/01.RES.0000182903.16652.d7 CrossRefPubMed

78.

Kurup S, Abramsson A, Li JP, Lindahl U, Kjellen L, Betsholtz C, Gerhardt H, Spillmann D (2006) Heparan sulphate requirement in platelet-derived growth factor B-mediated pericyte recruitment. Biochem Soc Trans 34(Pt 3):454–455. https://doi.org/10.1042/BST0340454 CrossRefPubMed

79.

Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M (2003) Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23(1):14–25CrossRefPubMedPubMedCentral

80.

Harrington LS, Sainson RC, Williams CK, Taylor JM, Shi W, Li JL, Harris AL (2008) Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. Microvasc Res 75(2):144–154. https://doi.org/10.1016/j.mvr.2007.06.006 CrossRefPubMed

81.

Beckstead BL, Santosa DM, Giachelli CM (2006) Mimicking cell-cell interactions at the biomaterial-cell interface for control of stem cell differentiation. J Biomed Mater Res A 79(1):94–103. https://doi.org/10.1002/jbm.a.30760 CrossRefPubMed

82.

Mouillesseaux KP, Wiley DS, Saunders LM, Wylie LA, Kushner EJ, Chong DC, Citrin KM, Barber AT, Park Y, Kim JD, Samsa LA, Kim J, Liu J, Jin SW, Bautch VL (2016) Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nat Commun 7:13247. https://doi.org/10.1038/ncomms13247 CrossRefPubMedPubMedCentral

83.

Simonavicius N, Ashenden M, van Weverwijk A, Lax S, Huso DL, Buckley CD, Huijbers IJ, Yarwood H, Isacke CM (2012) Pericytes promote selective vessel regression to regulate vascular patterning. Blood 120(7):1516–1527. https://doi.org/10.1182/blood-2011-01-332338 CrossRefPubMed

84.

Kelly-Goss MR, Sweat RS, Stapor PC, Peirce SM, Murfee WL (2014) Targeting pericytes for angiogenic therapies. Microcirculation 21(4):345–357. https://doi.org/10.1111/micc.12107 CrossRefPubMedPubMedCentral

85.

Gaengel K, Genove G, Armulik A, Betsholtz C (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29(5):630–638. https://doi.org/10.1161/ATVBAHA.107.161521 CrossRefPubMed

86.

Walpole J, Gabhann FM, Peirce SM, Chappell JC (2017) Agent-based computational model of retinal angiogenesis simulates microvascular network morphology as a function of pericyte coverage. Microcirculation. https://doi.org/10.1111/micc.12393 CrossRefPubMedPubMedCentral

87.

Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307(1):C25–C38. https://doi.org/10.1152/ajpcell.00084.2014 CrossRefPubMedPubMedCentral

88.

Ando K, Fukuhara S, Izumi N, Nakajima H, Fukui H, Kelsh RN, Mochizuki N (2016) Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish. Development 143(8):1328–1339. https://doi.org/10.1242/dev.132654 CrossRefPubMedPubMedCentral

89.

Hammes HP, Lin J, Wagner P, Feng Y, Vom Hagen F, Krzizok T, Renner O, Breier G, Brownlee M, Deutsch U (2004) Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53(4):1104–1110CrossRefPubMed

90.

Patan S (1998) TIE1 and TIE2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive microvascular growth. Microvasc Res 56(1):1–21. https://doi.org/10.1006/mvre.1998.2081 CrossRefPubMed

91.

Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87(7):1171–1180CrossRefPubMed

92.

Jeansson M, Gawlik A, Anderson G, Li C, Kerjaschki D, Henkelman M, Quaggin SE (2011) Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest 121(6):2278–2289. https://doi.org/10.1172/JCI46322 CrossRefPubMedPubMedCentral

93.

Iivanainen E, Nelimarkka L, Elenius V, Heikkinen SM, Junttila TT, Sihombing L, Sundvall M, Maatta JA, Laine VJ, Yla-Herttuala S, Higashiyama S, Alitalo K, Elenius K (2003) Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J 17(12):1609–1621. https://doi.org/10.1096/fj.02-0939com CrossRefPubMed

94.

Stratman AN, Schwindt AE, Malotte KM, Davis GE (2010) Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood 116(22):4720–4730. https://doi.org/10.1182/blood-2010-05-286872 CrossRefPubMedPubMedCentral

95.

Uebelhoer M, Natynki M, Kangas J, Mendola A, Nguyen HL, Soblet J, Godfraind C, Boon LM, Eklund L, Limaye N, Vikkula M (2013) Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB. Hum Mol Genet 22(17):3438–3448. https://doi.org/10.1093/hmg/ddt198 CrossRefPubMedPubMedCentral

96.

High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA (2008) Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci USA 105(6):1955–1959. https://doi.org/10.1073/pnas.0709663105 CrossRefPubMedPubMedCentral

97.

Cohen ED, Ihida-Stansbury K, Lu MM, Panettieri RA, Jones PL, Morrisey EE (2009) Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway. J Clin Invest 119(9):2538–2549. https://doi.org/10.1172/JCI38079 CrossRefPubMedPubMedCentral

98.

Peng Y, Yan S, Chen D, Cui X, Jiao K (2017) Pdgfrb is a direct regulatory target of TGFbeta signaling in atrioventricular cushion mesenchymal cells. PLoS ONE 12(4):e0175791. https://doi.org/10.1371/journal.pone.0175791 CrossRefPubMedPubMedCentral

99.

Bjarnegard M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A, Takemoto M, Gustafsson E, Fassler R, Betsholtz C (2004) Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131(8):1847–1857. https://doi.org/10.1242/dev.01080 CrossRefPubMed

100.

Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277(5323):242–245CrossRefPubMed

101.

Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadzic S, Zlokovic BV (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci. https://doi.org/10.1038/nn.4489 CrossRefPubMedPubMedCentral

102.

Trost A, Lange S, Schroedl F, Bruckner D, Motloch KA, Bogner B, Kaser-Eichberger A, Strohmaier C, Runge C, Aigner L, Rivera FJ, Reitsamer HA (2016) Brain and retinal pericytes: origin, function and role. Front Cell Neurosci 10:20. https://doi.org/10.3389/fncel.2016.00020 CrossRefPubMedPubMedCentral

103.

Sweeney MD, Ayyadurai S, Zlokovic BV (2016) Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 19(6):771–783. https://doi.org/10.1038/nn.4288 CrossRefPubMedPubMedCentral

104.

Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV (2015) Establishment and dysfunction of the blood-brain barrier. Cell 163(5):1064–1078. https://doi.org/10.1016/j.cell.2015.10.067 CrossRefPubMedPubMedCentral

Title: Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation
Authors: Jordan Darden
Laura Beth Payne
Huaning Zhao
John C. Chappell
Publication date: 01-02-2019
Publisher: Springer Netherlands
Published in: Angiogenesis / Issue 1/2019
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-018-9648-z

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STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

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