Vineetha Mathew, TUSM Candidate 2024, had an abstract accepted to the 14th International HHT Conference in October 2022 sponsored by the Cure HHT foundation (hyperlink to https://curehht.org/ ). The conference is only held every four years. The HHT Foundation also awarded Ms. Mathew a Young Scholar's Travel Award for travel costs.
Read the abstract of her paper below.
ADVANCING KNOWLEDGE ON THE EFFECTS AND PATHOGENESIS OF HEREDITARY HEMORRHAGIC TELANGIECTASIA IN PREGNANCY
Mathew V, Mei A, Joe A, Mann M, Kashpur O, Bhave S, Kapur N, Good M, Wallingford M.
Objective: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease distinguished by malformed vasculature. During pregnancy, undiagnosed HHT confers an increased risk for maternal mortality from vascular complications, although the underlying mechanism remains unknown. This study aims to evaluate placental expression of HHT-associated genes including ENG, ALK1, SMAD4, BMP9, and to explore placental vascular health and pathogenesis in HHT.
Methods: Immunofluorescence, proteomics, and in silico approaches in mouse and human placenta tissue were used to test the hypothesis that HHT gene expression in placenta is required for vascular integrity and conniving (CX43) expression. Morphology of placental vessels was evaluated in clinical biopsies as well as Eng. and Alk1 knock-out (KO) placenta.
Results: HHT proteins were detected throughout development in the placenta. Endothelial disruption and cellular disorganization were observed in HHT-affected human placental vessels (Fig. 1). Alk1 and Eng. null mice resulted in embryonic lethality. Embryonic day (E) 10.25 Alk1 and Eng. KO mouse placenta demonstrated micro hemorrhages, dilated vessels, and structural impairments. Additionally, Eng. KO showed loss of CX43 expression (Fig. 2).
Conclusion: Our findings support that HHT proteins facilitate placental vascular development. Embryonic lethality observed in preclinical models in conjunction with vascular disruption in HHT-affected human placenta denote HHT gene involvement in regulating vascular integrity necessary for development. Additionally, loss of CX43 in Eng. KO mice supports our hypothesis that conniving disruption may contribute to the pathological mechanism of HHT. Overall, this work will provide new insight into HHT mechanisms in pregnancy that will provide a basis for novel therapeutic targets.
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