The long-term goal of this laboratory is to understand the processes by which endothelial cells (ECs) regulate vessel stability and homeostasis. Our focus is to understand the functional relationship between the TGF-beta receptor ALK1 and its co-receptor, endoglin. These molecules are important regulators of angiogenesis and wound healing, and are the target genes for the vascular disease hereditary hemorrhagic telangiectasia (HHT). We will test the hypothesis that endoglin transduces TGF-beta receptor signals in endothelial cells via a novel Smad-independent mechanism. Our studies demonstrate that endoglin is phosphorylated by ALK1, which we hypothesize regulates endoglin?s effects on focal adhesion re-organization, cytoskeletal architecture, and migration in ECs. To understand this novel endoglin signaling pathway and its relevance in the vasculature, the aims of this proposal are:
Specific Aim 1 : Examine the consequences of TGF-beta receptor-mediated phosphorylation of endoglin to determine how this pathway regulates EC function. Studies will focus on the role of putative protein-protein interactions mediated by endoglin?s cytosolic domain, emphasizing the regulation of EC focal adhesion assembly, tubulogenesis, TGF-beta receptor subcellular localization, and EC-specific intercellular signals.
Specific Aim 2 : Examine the consequences of EC-targeted expression of endoglin CD mutants in the yolk sac vasculature.
This aim will emphasize cytosolic domain-dependent effects on EC tubulogenesis and angiogenic remodeling, and emphasize the endpoints used for Aim 1. The results obtained in these studies will elucidate the mechanism underlying endoglin?s regulation of intrinsic EC function as well as EC-initiated intercellular signals within the yolk sac vasculature in vivo.
Specific Aim 3 : Characterize the vascular abnormalities observed in the FVB:eng+/- mouse model.
This aim builds on new preliminary data which suggests that the heterozygous eng+/- expressed on the FVB mouse genetic background constitutes a potentially novel and useful model of HHT vascular malformation. We will study the structural and biochemical properties of the FVB:eng+/- vasculature in order to understand the basis for its vascular malformations. This model will then be used to test whether EC-expressed transgenic endoglin is sufficient to rescue the vascular deficiencies. Our proposed mouse transgenic, genetic, and biochemical models of endoglin function will lead to a deeper understanding of novel mechanisms of TGF-beta receptor-dependent regulation of EC proliferation, adhesion, tubulogenesis, and angiogenic remodeling that culminate in the establishment and maintenance of vessel integrity. The proposed studies are highly relevant to normal vascular function, and will elucidate endoglin's role in adult-onset vascular diseases.
|Duarte, Christine W; Black, Adam W; Lucas, F Lee et al. (2017) Cancer incidence in patients with hereditary hemorrhagic telangiectasia. J Cancer Res Clin Oncol 143:209-214|
|Caron, Jennifer M; Ames, Jacquelyn J; Contois, Liangru et al. (2016) Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope. Am J Pathol 186:1649-61|
|Young, K; Krebs, L T; Tweedie, E et al. (2016) Endoglin is required in Pax3-derived cells for embryonic blood vessel formation. Dev Biol 409:95-105|
|Ames, Jacquelyn J; Contois, Liangru; Caron, Jennifer M et al. (2016) Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway. J Biol Chem 291:2731-50|
|Young, Kira; Tweedie, Eric; Conley, Barbara et al. (2015) BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses. PLoS One 10:e0122892|
|Contois, Liangru W; Akalu, Abebe; Caron, Jennifer M et al. (2015) Inhibition of tumor-associated ?v?3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis 18:31-46|
|Duarte, Christine W; Murray, Kimberly; Lucas, F Lee et al. (2014) Improved survival outcomes in cancer patients with hereditary hemorrhagic telangiectasia. Cancer Epidemiol Biomarkers Prev 23:117-125|
|Gong, Yan; Yang, Xuehui; He, Qing et al. (2013) Sprouty4 regulates endothelial cell migration via modulating integrin *3 stability through c-Src. Angiogenesis 16:861-75|
|Contois, Liangru W; Nugent, Desiree P; Caron, Jennifer M et al. (2012) Insulin-like growth factor binding protein-4 differentially inhibits growth factor-induced angiogenesis. J Biol Chem 287:1779-89|
|Prudovsky, Igor; Vary, Calvin P H; Markaki, Yolanda et al. (2012) Phosphatidylserine colocalizes with epichromatin in interphase nuclei and mitotic chromosomes. Nucleus 3:200-10|
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