Topic Overview:
Arteriovenous malformations, or AVMs, are circulatory system defects that generally arise during embryonic or fetal development or soon after birth. Consisting of a tangled mass of vessels through which arteries connect directly to veins without an intervening capillary bed, these vascular shunts can, depending on size and location, cause ischemia, pain, stroke, and high-output cardiac failure. Although the vast majority of AVMs are sporadic in origin, of the estimated one in 5,000 individuals worldwide with hereditary hemorrhagic telangiectasia (HHT) types 1 and 2, AVMs are inherited in an autosomal dominant fashion and have been traced to gene mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively.

Dr. Roman studies vascular development and AVM formation using zebrafish as a model. With properties such as external fertilization and optical transparency, the zebrafish embryo offers a unique opportunity to study how AVMs arise. Through forward mutagenesis screens and generation of transgenic zebrafish lines, Dr. Roman developed a new vertebrate model for HHT 2, the zebrafish mutant violet beauregarde (vbg). Homozygous vbg mutants can easily be identified at two days post-fertilization by an abnormal circulation pattern in which most blood cells flow through a limited number of dilated cranial vessels and fail to perfuse the trunk and tail. Dr. Roman’s observations of the retention of primitive arteriovenous connections in response to increases in blood flow have defined a novel way in which AVMs can form. Using positional cloning and candidate gene testing, she localized the molecular basis for the vbg phenotype to a mutation in ALK1, a transforming growth factor-β receptor expressed predominantly in the arterial endothelium of cranial vessels. Dr. Roman further demonstrated that, in these vbg mutants, a greater than two-fold increase in endothelial cell number leads to cranial vessel enlargement, the first step in telangiectasia and AVM development.

Current and future directions for Dr. Roman’s research include elucidation of the precise signaling pathways for ALK1 and its downstream targets. The vbg zebrafish model for HHT 2 serves as a powerful tool for understanding vascular development, disease, and future treatment strategies.