Dreikorn, Erika
(2023)
The Cellular Mechanisms of AVM formation in Hereditary Hemorrhagic Telangiectasia.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Arteriovenous malformations (AVMs) directly connect arteries and veins and are a hallmark of the autosomal dominant disorder, hereditary hemorrhagic telangiectasia (HHT). The mutations that cause HHT alter activin receptor-like kinase 1 (ALK1, encoded by ACVRL1) signaling in endothelial cells (ECs). Despite knowledge of the affected signaling pathway, HHT treatments are limited to invasive procedures. A deeper understanding of disease mechanism is needed to develop pharmacological therapies for HHT.
Using an acvrl1 mutant zebrafish in which AVMs form in embryonic cranial vessels, we previously defined a two-step mechanism of AVM development involving 1) cell autonomous defects in arterial EC migration leading to increased EC number in and caliber of distal segments; and 2) flow-dependent enlargement of downstream arteries, analogous to the Circle of Willis, which directly feed an AVM. My goal was to understand “Step 2”, including cellular mechanisms, cell autonomy, and the role of blood flow.
I found that acvrl1 mutant AVMs occur with similar frequency in anterior and posterior positions along the Circle of Willis, and that AVMs, which are normally transient vascular segments that are retained in acvrl1 mutants, are not caused by disrupted arteriovenous identity. Using a pharmacological approach, I inhibited Alk1 signaling subsequent to pruning of these transient vessels and showed that AVMs still form, with feeding arteries co-opting alternative vessels. This result demonstrates that AVM location is not predetermined and that flow patterns dictate site selection. However, lowering blood viscosity did not rescue acvrl1 mutant AVMs, suggesting that the hemodynamic force of shear stress does not drive AVM growth. At the cellular level, I found that increased EC size explains enlargement of arteries and veins along the primary flow path. Because venous ECs do not express acvrl1, flow-dependent EC enlargement may be a cell nonautonomous effect with respect to acvrl1 mutation.
The true prevalence of HHT is unclear due to underdiagnosis, but it affects at least 1:5000 people worldwide and results in severe clinical outcomes and decreased quality of life. My work identifies cellular perturbations that underlie AVM formation that could be leveraged in development of new therapies for this underrecognized disease.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
9 May 2023 |
| Date Type: |
Publication |
| Defense Date: |
6 February 2023 |
| Approval Date: |
9 May 2023 |
| Submission Date: |
20 March 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
123 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Hereditary hemorrhagic telangiectasia (HHT)
acvrl1 mutant zebrafish
hemodynamics
BMP signaling |
| Date Deposited: |
10 May 2023 01:42 |
| Last Modified: |
10 May 2023 01:42 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44292 |
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