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.
