Vascular Smooth Muscle Cell Differentiation on Vertebrate Brain Arteries
Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics
First Advisor
Nicoli, Stefania
Abstract
Vertebrate brain arteries are wrapped by vascular smooth muscle cells (VSMCs), which are important for cerebral blood flow regulation and neurovascular coupling. VSMC dedifferentiation contributes to cerebrovascular diseases and neurodegeneration. Insights on VSMC differentiation during development may illuminate strategies to regenerate dedifferentiated VSMCs and alleviate cerebrovascular diseases and neurological disorders. In this dissertation, I investigated VSMC differentiation on the circle of Willis (CW), which consists of major arteries that supply blood to the vertebrate brain, with confocal live imaging of fluorescent transgenic zebrafish embryos. I found that arterial specification of CW endothelial cells (ECs) occurs after they migrate from cranial venous plexus to form CW arteries. VSMCs differentiate from pdgfrb+ mural cell progenitors after they are recruited to CW arteries. VSMC differentiation progressed spatiotemporally from anterior to posterior CW arteries. With genetic manipulation and drug treatment, I found that blood flow is required for VSMC differentiation on CW arteries. Flow responsive transcription factor klf2a is activated in ECs of CW arteries before VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CW arteries. klf2a likely promotes VSMC differentiation downstream of flow. Importantly, this work identifies flow activation of endothelial klf2a as a mechanism that contributes to VSMC differentiation on brain arteries.
Recommended Citation
Cheng, Siyuan, "Vascular Smooth Muscle Cell Differentiation on Vertebrate Brain Arteries" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1164.
https://elischolar.library.yale.edu/gsas_dissertations/1164
