DACH1 drives coronary artery development through shear stress-guided endothelial cell migration
Abstract/Contents
- Abstract
- Sufficient blood flow to tissues relies on arterial blood vessels, but the mechanisms regulating their development are poorly understood. Many arteries, including coronaries arteries of the heart, form through remodeling of an immature vascular plexus in a process triggered and shaped by blood flow. However, little is known about how cues from fluid shear stress are translated into responses that pattern artery development. Here, we show that mice lacking endothelial Dach1 have small coronary arteries, decreased endothelial cell polarization, and reduced expression of the chemokine Cxcl12. Under shear stress in culture, Dach1 overexpression stimulated endothelial cell polarization and migration against flow, which was reversed upon CXCL12/CXCR4 inhibition. In vivo, DACH1 was expressed during early arteriogenesis, but down in mature arteries. Mature artery-type shear stress (high, uniform laminar) specifically downregulated DACH1, while the remodeling artery-type flow (low, variable) maintained DACH1 expression. Together, our data support a model where DACH1 stimulates coronary artery growth by activating Cxcl12 expression and endothelial cell migration against blood flow into developing arteries. This activity is suppressed once arteries reach a mature morphology and acquire high, laminar flow that downregulates DACH1. Thus, we identify a mechanism by which blood flow quality balances artery growth and maturation. Furthermore, because we found DACH1 upregulation in endothelial cells at sites prone to atherosclerotic plaque formation, namely at arterial branch points, we then examined whether there is a link connecting endothelial DACH1 with atherosclerosis progression. Atherosclerosis is an artery disease that leads to narrower and hardened blood vessels over time. The cause is primarily due to the buildup of fatty lipids, cholesterol, and cellular debris, which then leads to plaque formation. Over time, the disease can progress, leading to a thickened plaque that can limit blood flow through affected arteries, or at worst result in potentially lethal artery blockage. Given the migratory signals induced by DACH1 during embryonic development, we hypothesize that endothelial DACH1 likely acts to activate endothelial cells at branch points and plaques to exacerbate atherosclerosis. We found robust endothelial and non-vascular DACH1 expression in these atheroprone regions, both at atherosclerotic plaques and at regions of directly perturbed blood flow. However, we were unable to ascertain a direct functional role of endothelial DACH1 on plaque progression using the ApoE and Dach1 deletion mouse models for atherosclerosis. Lastly, we examined the role of the membrane water channel Aquaporin1 in coronary vasculature development, since the gene was one of the top genes downregulated in Dach1 knockout mice and upregulated in Dach1 overexpressing endothelial cells. We found that Aquaporin1 is highly expressed in the remodeling zone of developing arteries, though the protein does not seem critical for proper coronary arteriogenesis. While the work is preliminary, our in vitro data suggest Aquaporin1 may also play a role in regulating endothelial cell motility under shear stress conditions.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Chang, Andrew Hsiu-Hao |
|---|---|
| Associated with | Stanford University, Department of Developmental Biology. |
| Primary advisor | Red-Horse, Kristy |
| Thesis advisor | Red-Horse, Kristy |
| Thesis advisor | Cyert, Martha S, 1958- |
| Thesis advisor | Dunn, Alexander Robert |
| Thesis advisor | Fuller, Margaret T, 1951- |
| Advisor | Cyert, Martha S, 1958- |
| Advisor | Dunn, Alexander Robert |
| Advisor | Fuller, Margaret T, 1951- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Andrew Hsiu-Hao Chang. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Andrew Hsiu-Hao Chang
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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