Notch Modulates VEGF Action in Endothelial Cells by Inducing Matrix Metalloprotease Activity

Overview

Journal Vasc Cell

Date 2011 Feb 26

PMID 21349159

Citations 41

Authors

Yasuhiro Funahashi

Carrie J Shawber

Anshula Sharma

Emi Kanamaru

Yun K Choi

Jan Kitajewski

Affiliations

Soon will be listed here.

Abstract

Background: In the vasculature, Notch signaling functions as a downstream effecter of Vascular Endothelial Growth Factor (VEGF) signaling. VEGF regulates sprouting angiogenesis in part by inducing and activating matrix metalloproteases (MMPs). This study sought to determine if VEGF regulation of MMPs was mediated via Notch signaling and to determine how Notch regulation of MMPs influenced endothelial cell morphogenesis.

Methods And Results: We assessed the relationship between VEGF and Notch signaling in cultured human umbilical vein endothelial cells. Overexpression of VEGF-induced Notch4 and the Notch ligand, Dll4, activated Notch signaling, and altered endothelial cell morphology in a fashion similar to that induced by Notch activation. Expression of a secreted Notch antagonist (Notch1 decoy) suppressed VEGF-mediated activation of endothelial Notch signaling and endothelial morphogenesis. We demonstrate that Notch mediates VEGF-induced matrix metalloprotease activity via induction of MMP9 and MT1-MMP expression and activation of MMP2. Introduction of a MMP inhibitor blocked Notch-mediated endothelial morphogenesis. In mice, analysis of VEGF-induced dermal angiogenesis demonstrated that the Notch1 decoy reduced perivascular MMP9 expression.

Conclusions: Taken together, our data demonstrate that Notch signaling can act downstream of VEGF signaling to regulate endothelial cell morphogenesis via induction and activation of specific MMPs. In a murine model of VEGF-induced dermal angiogenesis, Notch inhibition led to reduced MMP9 expression.

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References

Kitamura T, Ido Kitamura Y, Funahashi Y, Shawber C, Castrillon D, Kollipara R . A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J Clin Invest. 2007; 117(9):2477-85. PMC: 1950461. DOI: 10.1172/JCI32054. View

Bergers G, Brekken R, McMahon G, Vu T, Itoh T, Tamaki K . Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000; 2(10):737-44. PMC: 2852586. DOI: 10.1038/35036374. View

Nisato R, Hosseini G, Sirrenberg C, Butler G, Crabbe T, Docherty A . Dissecting the role of matrix metalloproteinases (MMP) and integrin alpha(v)beta3 in angiogenesis in vitro: absence of hemopexin C domain bioactivity, but membrane-Type 1-MMP and alpha(v)beta3 are critical. Cancer Res. 2005; 65(20):9377-87. DOI: 10.1158/0008-5472.CAN-05-1512. View

Uyttendaele H, Ho J, Rossant J, Kitajewski J . Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci U S A. 2001; 98(10):5643-8. PMC: 33266. DOI: 10.1073/pnas.091584598. View

Rowe R, Weiss S . Navigating ECM barriers at the invasive front: the cancer cell-stroma interface. Annu Rev Cell Dev Biol. 2009; 25:567-95. DOI: 10.1146/annurev.cellbio.24.110707.175315. View

Kopan R, Ilagan M . The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009; 137(2):216-33. PMC: 2827930. DOI: 10.1016/j.cell.2009.03.045. View

Seiki M, Mori H, Kajita M, Uekita T, Itoh Y . Membrane-type 1 matrix metalloproteinase and cell migration. Biochem Soc Symp. 2003; (70):253-62. DOI: 10.1042/bss0700253. View

Itokawa T, Nokihara H, Nishioka Y, Sone S, Iwamoto Y, Yamada Y . Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. Mol Cancer Ther. 2002; 1(5):295-302. View

Kato H, Taniguchi Y, Kurooka H, Minoguchi S, Sakai T, Tamura K . Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development. 1997; 124(20):4133-41. DOI: 10.1242/dev.124.20.4133. View

10.

Wang H, Olszewski B, Rosebury W, Wang D, Robertson A, Keiser J . Impaired angiogenesis in SHR is associated with decreased KDR and MT1-MMP expression. Biochem Biophys Res Commun. 2004; 315(2):363-8. DOI: 10.1016/j.bbrc.2004.01.059. View

11.

Shawber C, Das I, Francisco E, Kitajewski J . Notch signaling in primary endothelial cells. Ann N Y Acad Sci. 2003; 995:162-70. DOI: 10.1111/j.1749-6632.2003.tb03219.x. View

12.

Wagner S, Fueller T, Hummel V, Rieckmann P, Tonn J . Influence of VEGF-R2 inhibition on MMP secretion and motility of microvascular human cerebral endothelial cells (HCEC). J Neurooncol. 2003; 62(3):221-31. DOI: 10.1023/a:1023335732264. View

13.

Pepper M . Extracellular proteolysis and angiogenesis. Thromb Haemost. 2001; 86(1):346-55. View

14.

Shawber C, Kitajewski J . Notch function in the vasculature: insights from zebrafish, mouse and man. Bioessays. 2004; 26(3):225-34. DOI: 10.1002/bies.20004. View

15.

Sakai T, Taniguchi Y, Tamura K, Minoguchi S, Fukuhara T, Strobl L . Functional replacement of the intracellular region of the Notch1 receptor by Epstein-Barr virus nuclear antigen 2. J Virol. 1998; 72(7):6034-9. PMC: 110408. DOI: 10.1128/JVI.72.7.6034-6039.1998. View

16.

Deryugina E, Quigley J . Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006; 25(1):9-34. DOI: 10.1007/s10555-006-7886-9. View

17.

Kessenbrock K, Plaks V, Werb Z . Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010; 141(1):52-67. PMC: 2862057. DOI: 10.1016/j.cell.2010.03.015. View

18.

Hainaud P, Contreres J, Villemain A, Liu L, Plouet J, Tobelem G . The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res. 2006; 66(17):8501-10. DOI: 10.1158/0008-5472.CAN-05-4226. View

19.

Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E . Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 2004; 18(20):2474-8. PMC: 529534. DOI: 10.1101/gad.1239004. View

20.

Funahashi Y, Shawber C, Vorontchikhina M, Sharma A, Outtz H, Kitajewski J . Notch regulates the angiogenic response via induction of VEGFR-1. J Angiogenes Res. 2010; 2(1):3. PMC: 2828996. DOI: 10.1186/2040-2384-2-3. View