Regulation of Blood Vessel Formation and the Etiology of HHT
Blood vessel formation is a multi-step process. Endoglin is a TGFβ/ bone morphogenetic protein (BMP) coreceptor for the TGFβ/BMP receptor, ALK1, both of which are required for angiogenesis. In humans, haploinsufficiency of endoglin or ALK1 results in Hereditary Hemorrhagic Telangiectasia (HHT), a vascular disease characterized by a loss of arteriovenous identity and aberrant vSMC incorporation in fragile vessels.
Our research is focused on the roles of TGFβ/BMP signaling via endoglin and ALK1 in cardiovascular development and disease. Our work takes advantage of our state-of-the-art mass spectrometry core facility. Recent discoveries include BMP9-directed changes in endothelial cell protein chemokine signatures, including the regulation of SDF1 and MCP1 by BMP9 (Young et al., Blood, 2012) and BMP9 signaling crosstalk with the Hippo pathway, a regulator of endothelial cell mechanotransduction (Young et al., PLOS ONE 2015).
More recent interests include: 1) the interaction of the BMP and Notch signaling pathways in endothelial cell signaling, 2) the requirement for endoglin in embryonic vascular patterning carried out by Pax3-positive vascular cell progenitor cells (See Figure, “Targeted deletion of endoglin in Pax3-positive cells; e9.5 mouse embryonic intersomitic vessels), and 3) the role of BMP9 in the regulation of lipid metabolism.
A complete list of publications can be found on My NCBI
Endothelial cell signaling in cardiovascular development and disease. Our laboratory helped to establish endoglin functions in non-endothelial cell niches during embryonic development and in adult disease: we established: a functional role for endoglin in vascular smooth muscle cells arising from the neural crest, cell autonomous roles for endoglin in both endothelial and smooth muscle cells of developing blood vessels, and lymphatic vessels.
Tang Y, Urs S, Boucher J, Bernaiche T, Venkatesh D, Spicer DB, Vary CP, Liaw L. Notch and transforming growth factor-beta (TGFbeta) signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J Biol Chem. 2010;285(23):17556-63. PMCID:2878520.
Mancini ML, Verdi JM, Conley BA, Nicola T, Spicer DB, Oxburgh LH, Vary CP. Endoglin is required for myogenic differentiation potential of neural crest stem cells. Dev Biol. 2007;308(2):520-33. PMCID:2041841.
Mouta-Bellum C, Kirov A, Miceli-Libby L, Mancini ML, Petrova TV, Liaw L, Prudovsky I, Thorpe PE, Miura N, Cantley LC, Alitalo K, Fruman DA, Vary CP. Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha. Dev Dyn. 2009;238(10):2670-9. PMCID:2826787.
Mancini ML, Terzic A, Conley BA, Oxburgh LH, Nicola T, Vary CP. Endoglin plays distinct roles in vascular smooth muscle cell recruitment and regulation of arteriovenous identity during angiogenesis. Dev Dyn. 2009;238(10):2479-93. PMCID:2947792.
Novel endoglin-dependent protein expression changes in the vasculature. We contributed to the identification of novel endoglin-dependent functions. Most recently we employed state-of-the-art mass spectrometric approaches to discover and quantify novel endoglin signaling targets, including, endoglin-dependent cancer stromal cell expression of novel proteins such as IGFBP4, and BMP9/endoglin/ALK1-dependent alteration of the SDF1/CXCR4 axis in endothelial cells, conducted in collaboration with Dr. Liaw.
Santibanez JF, Letamendia A, Perez-Barriocanal F, Silvestri C, Saura M, Vary CP, Lopez-Novoa JM, Attisano L, Bernabeu C. Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J Cell Physiol. 2007;210(2):456-68.
Jerkic M, Rivas-Elena JV, Santibanez JF, Prieto M, Rodriguez-Barbero A, Perez-Barriocanal F, Pericacho M, Arevalo M, Vary CP, Letarte M, Bernabeu C, Lopez-Novoa JM. Endoglin regulates cyclooxygenase-2 expression and activity. Circ Res. 2006;99(3):248-56.
Young K, Conley B, Romero D, Tweedie E, O’Neill C, Pinz I, Brogan L, Lindner V, Liaw L, Vary CP. BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. Blood. 2012;120(20):4263-73. PMCID:3501721.
Young K, Tweedie E, Conley B, Ames JJ, FitzSimons M, Brooks P, Liaw L, Vary CPH. BMP9 crosstalk with the Hippo pathway regulates endothelial cell matricellular and chemokine responses. PLoS ONE. 2015; Apr 24;10(4):e0122892.