Regulation of ALK1 Signaling in the Endothelium
Abstract
Topic Area: This proposal addresses the topic area of Vascular Malformations. The blood vascular system is an ordered series of interconnected tubes that carry blood and nutrients to all cells of the body. Large arterial vessels carry oxygenated blood away from the heart and deliver it to highly branched networks of tiny, thin-walled vessels called capillaries. In the capillary networks, blood flow slows dramatically and oxygen diffuses from the blood to surrounding tissues to fuel nearby cells. De-oxygenated blood then enters veins, which carry it back to the heart. During embryonic development, mistakes can occur in interpreting the blueprint of this complex system, resulting in vascular malformations (VMs). VMs range widely in size and complexity and can cause many different health problems. Our research is focused on a specific type of VM known as an arteriovenous malformation (AVM). AVMs are direct connections between arteries and veins; in other words, these vessels are not separated by tiny capillaries. Some AVMs are fragile and prone to rupture: for example, ruptured AVMs inside the nose can cause severe nosebleeds, and ruptured AVMs in the brain can cause stroke. Other AVMs can cause problems even if they do not rupture: for example, lung AVMs can allow bacteria to reach brain vessels, leading to brain infection, and liver AVMs can lead to heart failure. Some AVMs form during embryonic development and may grow from small, silent lesions to large, life-threatening malformations. Other AVMs can form de novo throughout life. Despite the morbidity and mortality associated with these lesions and the ample opportunity for intervention, there are no medical therapies that specifically target AVM growth or prevent new AVMs from forming. Development of drugs that specifically target AVMs is hindered by a number of knowledge gaps regarding how and why AVMs form. Overview of research project: We study AVM development through the lens of the prototype AVM disease, hereditary hemorrhagic telangiectasia (HHT). HHT is a genetic disease caused primarily by mutations in one of two genes, ACVRL1 or ENG. Although all of our cells contain the same DNA and therefore the same genes, different cell types express different genes. In the case of ACVRL1 and ENG, these genes are transcribed to RNA and translated to protein primarily in endothelial cells, which form the inner lining of blood vessels. Broadly, the goal of our research is to understand the mistakes made by endothelial cells that lead to AVMs in HHT. These include “molecular” mistakes, in which endothelial cells fail to properly integrate instructive cues from their surroundings to launch expression of all of the right genes. Molecular mistakes ultimately lead to “cellular” mistakes, or inappropriate cell behaviors. Using a zebrafish model of HHT (ACVRL1 mutants), we discovered that blood flow is required to “turn on” ACVRL1 gene expression, and that ACVRL1 mutations impair the ability of arterial endothelial cells to hang on to their surroundings and resist movement in the direction of blood flow. These cells are therefore “pushed” toward capillaries, ultimately ballooning these tiny blood vessels into larger blood vessels that connect directly to veins. In other words, misdirected endothelial cell movement leads to development of AVMs. It is clear from our work that mutations associated with HHT interfere with the endothelial cell’s ability to sense and respond to blood flow. In this application, we aim to uncover the mechanism by which blood flow turns on ACVRL1 expression and potentiates the cellular activity of the protein produced by ACVRL1, which is known as ALK1. Drugs that mimic these important effects of blood flow may serve to overcome ALK1 signaling deficiency in some HHT patients. Additionally, we will determine which genes are “turned on” in response to blood flow-induced ALK1 activation, and whether restoring expression of these genes in HHT mutant cell
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110352
Entities
People
- Beth L Roman
Organizations
- United States Army
- University of Pittsburgh