Cynthia St Hilaire, PhD
Cynthia St Hilaire, PhD
Assistant Professor of Medicine,
Assistant: Diane Margaria
BS - Molecular Genetics
University of Vermont, 2001
PhD - Biochemistry, Program in Cell & Molecular Biology
Boston University School of Medicine, 2008
Postdoctoral Fellow - Vascular Biology
National Heart, Lung, and Blood Institute, 2015
My research program stems from the discovery of the rare monogenetic disease, Arterial Calcification due to Deficiency of CD73 (ACDC; OMIM #211800). Patients with ACDC have a history of cramping pain in their calves, thighs, and buttocks. They have chronic ischemic pain in their feet, and can only walk a short distance before discomfort compels them to stop. Imaging and pathological studies showed extensive calcification in their lower-extremity arteries, localized to the medial layer (Figs. 1 & 2). Additionally, a pathological study of an ACDC patient vessel showed evidence of medial dysplasia, stenosis, and arteriomegaly. The phenotypes in ACDC are shared in a handful of more common diseases and disorders, which highlights the importance of using insights into rare genetic diseases as a means to identify new genotype-to-phenotype relationships that are often hard to pinpoint in common disease pathologies.
Patients with ACDC harbor genetic mutations in the gene 5’-ectonucleotidase, which encodes for the protein CD73. CD73 is an enzyme that acts one step downstream of enzymes ENPP1 and CD39 in extracellular ATP metabolism, converting AMP to adenosine (Fig. 3). The mutations identified in ACDC patients result in loss of CD73 enzymatic activity, diminishing extracellular adenosine production. Adenosine acts as a signaling molecule in a variety of cellular processes via binding adenosine receptors (A1, A2a, A2b, and A3). Adenosine is described as a “retaliatory metabolite” as it is generated extracellularly in response to stresses like shear flow, mechanical stress, inflammation, and hypoxia, and has been found to elicit protective responses to these adverse conditions in the vasculature. These stresses are continuously present in vessels, and the release and breakdown of ATP to adenosine activates pathways that allow cells to adapt to these stresses. Our general hypothesis is that the deleterious phenotypes in ACDC vasculature occur due to a lack of adenosine signaling. Supporting this postulation, I developed an in vitro disease model showing that lack of CD73 results in calcification, which is reversed with genetic rescue, and significantly reduced with exogenous adenosine treatment (Fig. 4). This discovery is the first to link adenosine and ectopic calcification.
Research conducted in my lab will explore the role of CD73 and adenosine signaling in complex vascular pathologies in vitro (primary human and mouse cells and patient-specific induced-pluripotent stem cells) and in vivo (genetically defined murine models and surgical manipulations), with the goal of translating our findings in ACDC to more common vascular diseases and pathologies.
St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, Carlson-Donohoe H, Lederman RJ, Chen MY, Yang D, Siegenthaler MP, Arduino C, Mancini C, Freudenthal B, Stanescu HC, Zdebik AA, Chaganti RK, Nussbaum RL, Kleta R, Gahl WA, Boehm M. NT5E mutations and arterial calcifications. N Engl J Med. 2011 Feb 3;364(5):432-42. PubMed PMID: 21288095; PubMed Central PMCID: PMC3049958.
Markello TC, Pak LK, St Hilaire C, Dorward H, Ziegler SG, Chen MY, Chaganti K, Nussbaum RL, Boehm M, Gahl WA. Vascular pathology of medial arterial calcifications in NT5E deficiency: Implications for the role of adenosine in pseudoxanthoma elasticum. Mol Genet Metab. 2011 May;103:44-50. PMID 21371928.
Cooley BC, Nevado J, Mellad J, Yang D, St Hilaire C, Negro A, Fang F, Chen G, San H, Walts AD, Schwartzbeck RL, Taylor B, Lanzer JD, Wragg A, Elagha A, Beltran LE, Berry C, Feil R, Virmani R, Ladich E, Kovacic JC, Boehm M. TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med. 2014 Mar 12;6(227):227ra34. PubMed PMID: 24622514; PubMed Central PMCID: PMC4181409.
Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CC, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014 Aug 7;371(6):507-18. PubMed PMID: 25029335; PubMed Central PMCID: PMC4174543.
P. Lanzer, M. Boehm, V. Sorribas, M. Thiriet, J. Janzen, T. Zeller, C. St. Hilaire, C. Shanahan. Medial vascular calcification revisited: review and perspectives. Eur Heart J. 2014 Jun 14;35(23):1515-1525. PMID 24740885.
Boehm M, St. Hilaire C. Vascular Genetics. In: Lanzer P. (Ed.) PanVascular Medicine, 2nd edition, vol.x, pp 53-88. Springer Heidelberg New York Dordrecht London, 2015. DOI: 10.1007/978-3-642-37393-0_4-1