UNCOVERING THE COMBINED EFFECTS OF VEGFA AND ANG2 PRO-ANGIOGENIC SIGNALING IN HEREDITARY HEMORRHAGIC TELANGIECTASIA - UNCOVERING THE COMBINED EFFECTS OF VEGFA AND ANG2 PRO-ANGIOGENIC SIGNALING IN HEREDITARY HEMORRHAGIC TELANGIECTASIA Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic vascular disease with no cure. HHT is characterized by abnormalities in blood vessels that occur in mucocutaneous tissues (telangiectasias) and deep tissues (arteriovenous malformations, AVMs). The tangled, enlarged, fragile and aberrant vasculature in HHT patients is prone to sudden or chronic bleeding. Sudden hemorrhaging of AVMs in brain, lungs or liver may cause serious complications and even death. While diagnosed AVMs can be surgically treated, there are no FDA approved drugs to prevent or manage them. Developing therapeutics to manage AVMs has been especially challenging as the mechanism of AVM formation is not clearly understood. Increased VEGF-VEGFR2 and ANG2–TIE2 pro-angiogenic signaling pathways have been indicated in abnormal vascular malformation in HHT. Both signaling cascades have been separately inhibited to demonstrate beneficial effects in HHT mouse models. Furthermore, VEGFA inhibitor—Bevacizumab—has been semi-successfully used to manage chronic nose bleeds in HHT patients. Although unknown in HHT, there have been reports of these signaling pathways working in concordance in other vascular pathologies. Thus, my working hypothesis is that dual VEGFA-ANG2 inhibition will have a superior beneficial effect on AVM suppression compared to monotherapies in HHT. To test this hypothesis, my proposed central aim is to evaluate the molecular effectiveness of a dual inhibitor over individual inhibition in normalizing vascular malformations in an HHT mouse model. I will utilize a bispecific VEGFA-ANG2 inhibitor, VEGFA inhibitor and ANG2 inhibitor in a comparison study focused on the Smad4 HHT mouse model. I will begin by determining minimal effective dosage of each inhibitor that normalizes VEGFA and ANG2 levels postnatally after Smad4 deletion. Next, I will comprehensively assess surface and whole brain vasculature, as well as retinal blood vessels, to compare phenotypic effects of each inhibitor via vascular latex casting, light sheet microscopy and immunofluorescent staining methods. Lastly, I will investigate transcriptomic and molecular changes and determine the potential role of various downstream signaling pathways. Overall, this study will further the mechanistic understanding of AVM development and explore potential therapeutic options for HHT treatment. This project will also advance my scientific training goals as the Principal Investigator, with focus on improving my breadth of scientific knowledge, approach to study design and project management, and building mastery of key technical skills. As a trainee, I will also further my experience in various ways of scientific communication, including presenting at conferences and manuscript writing. I will benefit from the mentorship of a highly experienced sponsor and extensive resources at a prestigious research University.
