Notch functions to modulate cell-fate decisions during vascular development. The overall objectives are to define roles for Notch during sprouting of blood vessels and remodeling. We explore the hypothesis that angiogenesis is regulated by cross-talk between Notch and integrin signaling pathways;that is we ask if Notch regulation of integrin expression is key to control of endothelial migration, tubulogenesis and sprouting. Our preliminary results show Notch suppresses expression of a2b1 and a6b4 integrins, known angiogenic regulators.
In Aim I, we use in vitro assays to explore the consequences of Notch suppression of a2 and a6b4 expression. We propose (1) Notch suppresses a2b1 to affect endothelial migration and/or tube formation in association with collagens/laminins, and (2) Notch suppresses a6/b4 to affect endothelial migration and sprouting in association with laminins. In vitro assays will determine if one can reverse the Notch-suppression of angiogenesis by ectopic expression of a2, b4 and/or a6 integrins.
In Aim II, we utilize mice to explore genetic interaction between Notch and integrins, using mice deficient in a2 integrin or defective in b4 signaling, crossed to mice defective for Notch.
Notch signaling is fundamental to proper vascular development. We present data strongly implicating Notch as a regulator of sprouting angiogenesis and lymphatic function. Thus, the studies will aid us in understanding the functions of Notch in during pathological angiogenesis and lymphatic differentiation and may assist in developing strategies and therapeutics to correct lymphatic disorders or block tumor angiogenesis or lymphangiogenesis.
|Kangsamaksin, Thaned; Murtomaki, Aino; Kofler, Natalie M et al. (2015) NOTCH decoys that selectively block DLL/NOTCH or JAG/NOTCH disrupt angiogenesis by unique mechanisms to inhibit tumor growth. Cancer Discov 5:182-97|
|Kangsamaksin, Thaned; Tattersall, Ian W; Kitajewski, Jan (2014) Notch functions in developmental and tumour angiogenesis by diverse mechanisms. Biochem Soc Trans 42:1563-8|
|England, Ryan W; Hardy, Krista L; Kitajewski, Alex M et al. (2014) Propranolol promotes accelerated and dysregulated adipogenesis in hemangioma stem cells. Ann Plast Surg 73 Suppl 1:S119-24|
|Pajvani, Utpal B; Qiang, Li; Kangsamaksin, Thaned et al. (2013) Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat Med 19:1054-60|
|Tung, Jennifer J; Tattersall, Ian W; Kitajewski, Jan (2012) Tips, stalks, tubes: notch-mediated cell fate determination and mechanisms of tubulogenesis during angiogenesis. Cold Spring Harb Perspect Med 2:a006601|
|Wong, Alvin; Hardy, Krista L; Kitajewski, Alex M et al. (2012) Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plast Reconstr Surg 130:1012-21|
|Kofler, Natalie M; Shawber, Carrie J; Kangsamaksin, Thaned et al. (2011) Notch signaling in developmental and tumor angiogenesis. Genes Cancer 2:1106-16|
|Kitajewski, Jan (2011) Fine-tuning endothelial Notch: SIRT-ainly an unexpected mechanism. Dev Cell 20:577-8|
|Boscolo, Elisa; Stewart, Camille L; Greenberger, Shoshana et al. (2011) JAGGED1 signaling regulates hemangioma stem cell-to-pericyte/vascular smooth muscle cell differentiation. Arterioscler Thromb Vasc Biol 31:2181-92|
|Hunkapiller, Nathan M; Gasperowicz, Malgorzata; Kapidzic, Mirhan et al. (2011) A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia. Development 138:2987-98|
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