Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder with a prevalence of 1 in 5000 that is caused by ENG, ALK1, or SMAD4 haploinsufficiency. These genes encode proteins important in endothelial bone morphogenetic protein (BMP) signaling, which is required to prevent development of fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). In HHT patients, AVMs develop throughout life in skin, nasal mucosa, gastrointestinal (GI) tract, and liver and can lead to epistaxis, hemorrhage, anemia, and high-output heart failure. Congenital lesions in lung and brain may lead to brain abscess or stroke. Currently available medications for HHT patients block angiogenesis or enhance clotting. These therapeutics are not ideal: they decrease epistaxis and GI bleeds in some but not all patients and are ineffective against potentially life-threatening congenital lesions in the brain and lung. Furthermore, these agents may delay wound healing and enhance risk of severe hemorrhage and thrombotic events. Therefore, the goal of our research program is to understand HHT disease mechanism to support development of targeted medical therapies for this disease. Using a zebrafish alk1 mutant as an HHT2 model, we uncovered a two-step mechanism of AVM development. In Step 1, loss of flow-dependent Alk1 signaling enhances endothelial cell migration in the direction of flow within lumenized arteries. This aberrant migration skews endothelial cell distribution toward and enlarges caliber of more distal arterial segments. In Step 2, normally transient artery-vein connections downstream of enlarged arterial segments are retained in a flow-dependent manner, resulting in high-flow AVMs. In this work, we will explore the mechanisms that underlie these two independent flow-based signaling pathways, the first of which is abrogated with Alk1 loss, and the second of which is intact with Alk1 loss.
In Aim 1, we will combine developmental biology and biomechanics approaches to determine whether flow-dependent Alk1 signaling governs arterial endothelial cell migration via control of planar cell polarity or generation of endothelial tension in live zebrafish embryos.
In Aim 2, we will use zebrafish embryos and a novel microfluidic platform seeded with human endothelial cells to dissect the roles of two components of blood flow?the heart-derived circulating ALK1 ligand, BMP10, and the mechanical force of shear stress?in flow- and Alk1-dependent retrograde arterial endothelial cell migration.
In Aim 3, we will test the hypothesis that AVMs represent an adaptive response to altered hemodynamic force and address the signaling mechanisms that underlie flow-dependent AVM development. These studies will shed new light on two distinct flow-dependent pathways important for HHT-associated AVM development. Mechanistic information gleaned from this work can be used to develop targeted therapeutics that 1) stop development of new AVMs by repairing flow-dependent ALK1 signaling and normalizing endothelial cell migration, or 2) slow phenotype progression by preventing flow-dependent enlargement of existing AVMs.
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease associated with abnormal blood vessel connections, known as arteriovenous malformations (AVMs), which can cause anemia, stroke, or heart failure. Current medicines available to HHT patients are not specific to disease mechanism: they stop all new blood vessels from forming or enhance blot clotting and carry risk of severe bleeding or embolic stroke. The goal of our research is to understand how HHT-associated AVMs develop and ultimately to apply this knowledge to the design of targeted, safe medications that decrease morbidity and mortality in HHT patients.
| Roman, Beth L; Hinck, Andrew P (2017) ALK1 signaling in development and disease: new paradigms. Cell Mol Life Sci 74:4539-4560 |
