Establishment of a vascular system is a key requirement for the development and survival of the mammalian embryo. In the adult, deregulation of vascular growth contributes to the pathology of devastating disorders including but not restricted to cancer. Dr. M. Luisa Iruela-Arispe and her colleagues are interested in understanding the process by which blood vessels are formed and its regulation in vivo. Specifically, research efforts focus on four subjects.
The first is angiogenesis inhibitors. Using a combination of transgenic mouse models, biochemistry and cell biology, the researchers investigate the biological function of thrombospondin-1, ADAMTS1 and ADAMTS8, all potential endogenous inhibitors of angiogenesis. Experiments are also designed to ascertain their potential therapeutic value in the suppression of tumor growth.
The second subject is the contribution of Notch1 to vascular morphogenesis. Recent linkage and knock-out studies have revealed that Notch signaling is required for morphogenesis and homeostasis of the vascular system. Using a Cre-lox strategy, the researchers are inactivating Notch1 from endothelial and smooth muscle cells. These experiments are complementary to expression arrays and several modalities of signaling studies in vitro.
Iruela-Arispe’s lab also examines the regulation of vascular endothelial growth factor availability. The researchers have recently found that specific proteases part take in the removal of VEGF from the matrix by cleaving the growth factor directly and releasing bioactive peptides. This release is dose-dependent and it is suppressed by specific inhibitors. [paragraph] Proteolytically processed VEGF is able to phosphorylate its receptors at the same molar ratio as the entire molecule. The biological significance of these findings is being studied with transgenic mice expressing different VEGF mutants.
The last subject of study is the role of progesterone receptor signaling in endothelial cells. Steroid hormones are essential for endometrial cycle, ovulation, implantation and lactation. In addition, they play significant roles in the cardiovascular system. Yet, relatively little is known about their effects on vascular cells. The researchers are focusing on the role of progesterone receptor on endothelial cell biology using a combination of transgenic mouse models and signaling experiments in vitro.
Selected Cancer-Related Publications:
Chen TT, Luque A, Lee S, Anderson SM, Segura T, Iruela-Arispe ML. Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J Cell Biol. 2010 Feb 22;188(4):595-609.
Zovein AC, Luque A, Turlo KA, Hofmann JJ, Yee KM, Becker MS, Fassler R, Mellman I, Lane TF, Iruela-Arispe ML. Beta1 integrin establishes endothelial cell polarity and arteriolar lumen formation via a Par3-dependent mechanism. Dev Cell. 2010 Jan 19;18(1):39-51.
da Silva RG, Tavora B, Robinson SD, Reynolds LE, Szekeres C, Lamar J, Batista S, Kostourou V, Germain MA, Reynolds AR, Jones DT, Watson AR, Jones JL, Harris A, Hart IR, Iruela-Arispe ML, Dipersio CM, Kreidberg JA, Hodivala-Dilke KM. Endothelial alpha3beta1-integrin represses pathological angiogenesis and sustains endothelial-VEGF. Am J Pathol. 2010 Sep;177(3):1534-48. Epub 2010 Jul 16.
Stockmann C, Kerdiles Y, Nomaksteinsky M, Weidemann A, Takeda N, Doedens A, Torres-Collado AX, Iruela-Arispe L, Nizet V, Johnson RS. Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4329-34. Epub 2010 Feb 8.
Lee YJ, Koch M, Karl D, Torres-Collado AX, Fernando NT, Rothrock C, Kuruppu D, Ryeom S, Iruela-Arispe ML, Yoon SS. Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1. Cancer Res. 2010 Feb 1;70(3):948-56. Epub 2010 Jan 26.