Hemodynamics regulate spatiotemporal artery muscularization in the developing circle of Willis

Author:

Cheng Siyuan123ORCID,Xia Ivan Fan123ORCID,Wanner Renate123,Abello Javier4,Stratman Amber N4ORCID,Nicoli Stefania123ORCID

Affiliation:

1. Department of Genetics, Yale School of Medicine

2. Yale Cardiovascular Research Center, Section of Cardiology, Department of Internal Medicine, Yale School of Medicine

3. Vascular Biology & Therapeutics Program, Yale School of Medicine

4. Department of Cell Biology & Physiology, School of Medicine, Washington University in St. Louis

Abstract

Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration from cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors after they were recruited to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity and wall shear stress. Furthermore, pulsatile flow induces differentiation of human brain PDGFRB+ mural cells into VSMCs, and blood flow is required for VSMC differentiation on zebrafish CoW arteries. Consistently, flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight blood flow activation of endothelial klf2a as a mechanism regulating initial VSMC differentiation on vertebrate brain arteries.

Funder

National Institutes of Health

American Heart Association

Publisher

eLife Sciences Publications, Ltd

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