In hereditary hemorrhagic telangiectasia (HHT), arteriovenous malformations (AVMs) in multiple organs and telangiectasia are the major pathological lesions causing recurrent spontaneous hemorrhage that can be life- threatening and leads to long-term disability. A prevailing view is that HHT is caused by haploinsufficiency in somatic endothelial cells (ECs) of one of its causative genes, such as endoglin (ENG, an accessory receptor of TGF/BMP) in HHT1 or ALK1 (ACVLR1, a type 1 receptor of TGF/BMP) in HHT2. However, studies by us and others suggest that gene haploinsufficiency in somatic EC alone is inadequate to explain AVM development and progression and the variations in HHT phenotypes. Instead, our data support the hypotheses that AVM development and progression result from an interplay of several factors: (1) a dose-dependent homozygous loss-of-function of ENG or ALK1 in ECs; (2) contribution of EC and macrophage derived from hematopoietic stem cells (HSC); and (3) pro-inflammatory phenotype of HHT monocytes and macrophages. We have developed several mouse models that have AVMs in multiple organs, replicating the human HHT phenotype. We will use these models and blood specimens from HHT patients provided by HHT Center in St. Michael's hospital of University of Toronto to test these hypotheses.
In Aim 1 we will use HHT1 and HHT2 mouse models and a novel lung organoid model to determine if the quantity of Eng- or Alk1-null EC required for AVM formation is different among organs and is positive correlate with lesion severity.
In Aim 2, we will use HSC transplantation experiments to determine the roles of HSC-derived Alk1- or Eng-null ECs and macrophages in AVM initiation and progression.
In Aim 3, we will use both mouse models and blood monocytes from HHT patients to investigate how HHT monocytes and macrophages promote AVM progression. This project will be the first systematic investigation of the cell types involved in AVM formation and progression. The accomplishment of our specific aims will lead to a paradigm shift on our understanding of how AVMs form in HHT patients. The results of our proposed studies will lead to a fuller knowledge of the basic mechanisms of AVM pathogenesis in HHT, and put us in a much better position to design specific therapies. Validation of the mechanisms being tested in this project can lead to potential therapies that can be tested in pre-clinical trials. This would be a significant advance for the field since therapeutic options for HH patients are currently very limited.

Public Health Relevance

Hereditary Hemorrhagic Telangiectasia (HHT) patients have arteriovenous malformations (AVM) in multiple organs and skin that can cause repeated and uncontrolled bleeding. It is currently not know how AVM formed and no specific medical therapy available for treating the patients. These studies will use our novel mouse AVM models and blood from HHT patients to study how AVM formed, and to identify new targets that can be used for developing new therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Mcdonald, Cheryl
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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