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ALK1 ligand requirements for prevention of arteriovenous malformations

Rosato, Teresa (2022) ALK1 ligand requirements for prevention of arteriovenous malformations. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Arteriovenous malformations (AVMs) are direct connections between arteries and veins that may cause bleeding, anemia, hypoxemia, stroke, and heart failure. To understand how AVMs develop, we study the autosomal dominant disease, hereditary hemorrhagic telangiectasia (HHT). HHT-associated AVMs are caused by defective bone morphogenetic protein (BMP) signaling through the endothelial cell receptor, ALK1. BMP ligands are generated as proproteins that require furin processing to release the N-terminal prodomain from the C-terminal growth factor (GF) domain. Although BMP9 and BMP10 GF domain homodimers and heterodimers similarly activate ALK1 in vitro, the genetic requirements for BMP9 and BMP10 with respect to AVM prevention are unclear, and the precise molecular nature of circulating ALK1 ligands is not known.
Using zebrafish genetic models, I identified Bmp10 as the only Alk1 ligand required for vascular homeostasis and AVM prevention throughout life: with age, zebrafish bmp10 mutants develop skin and liver vascular malformations and heart failure, similar to HHT patients. Moreover, I found that the predominant form of BMP10 in human plasma is unprocessed, full-length proBMP10, and that the physiologically relevant form of circulating proBMP10 may be a monomer or heterodimer with BMP9 GF.
Because BMP9 and BMP10 are liver-derived circulating proteins, we reasoned that these ligands may compose the “hepatic factor,” found in high concentrations in hepatic venous effluent, that is required to prevent development of lung AVMs after the Glenn procedure. This palliative surgery performed in single-ventricle patients excludes inferior vena cava flow from pulmonary circulation. Although my results fail to support BMP9 and BMP10 as “hepatic factor,” per se, they suggest that decreased ALK1 signaling may play some role in lung AVM development in this population.
Improving quality of life for HHT and Glenn patients is an unmet public health need. Despite our understanding of the signaling pathway affected, there are no pharmacological therapies that restore ALK1 signaling flux in these patients. In HHT, therapeutic strategies currently focus on general inhibition of angiogenesis or administration of recombinant GF dimers. My work suggests that development of targeted therapeutics for HHT should focus on proBMP10.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Rosato, Teresatlc53@pitt.edutlc530000-0002-5558-773X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoman, Bethromanb@pitt.eduromanb
Committee MemberZsolt, Urbanurbanz@pitt.eduurbanz
Committee MemberGross, Jeffreygrossjm@pitt.edugrossjm
Committee MemberHinck, Andrewahinck@pitt.eduahinck
Date: 10 May 2022
Date Type: Publication
Defense Date: 26 January 2022
Approval Date: 10 May 2022
Submission Date: 21 February 2022
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 136
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: bone morphogenetic proteins, vascular development, hereditary hemorrhagic telangiectasia, zebrafish, enzyme-linked immunosorbent assay, arteriovenous malformation, Glenn procedure
Date Deposited: 10 May 2022 18:10
Last Modified: 10 May 2022 18:10
URI: http://d-scholarship.pitt.edu/id/eprint/42226

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