Endothelial mechanosensing: A forgotten target to treat vascular remodeling in hypertension?

Tiezzi, Margherita; Deng, Hanqiang; Baeyens, Nicolas

doi:10.1016/j.bcp.2022.115290

Cited by 2 publications

(1 citation statement)

References 133 publications

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“…An important aspect of this homeostatic regulation involves sensing of fluid shear stress (FSS) from blood flow by vascular endothelial cells (ECs) 1,2 . ECs encode a FSS set point such that sustained FSS above or below this level triggers vessel outward or inward remodeling to increase or decrease lumen diameter and restore FSS to the initial level 3,4 . Available evidence suggests that FSS near the set point activates signaling and gene expression programs that stabilize the vessel, whereas FSS above or below this range destabilizes the vessel to permit remodeling.…”

Section: Introductionmentioning

confidence: 99%

cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling

Deng,

Rukhlendo,

Joshi

et al. 2023

Preprint

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Fluid shear stress (FSS) from blood flow is sensed by vascular endothelial cells (ECs) to determine vessel stability, remodeling and susceptibility to atherosclerosis and other inflammatory diseases but the regulatory networks that govern these behaviors are only partially understood. We used cSTAR, a powerful new computational method, to define EC transcriptomic states under low shear stress (LSS) that triggers vessel inward remodeling, physiological shear stress (PSS) that stabilizes vessels, high shear stress (HSS) that triggers outward remodeling, and oscillatory shear stress (OSS) that confers disease susceptibility, all in comparison to cells under static conditions (STAT). We combined these results with the LINCS database where EC transcriptomic responses to drug treatments to define a preliminary regulatory network in which the cyclin-dependent kinases CDK1/2 play a central role in promoting vessel stability. Experimental analysis showed that PSS induced a strong late G1 cell cycle arrest in which CDK2 was activated. EC deletion of CDK2 in mice resulted in inward artery remodeling and both pulmonary and systemic hypertension. These results validate use of cSTAR to determine EC state and in vivo vessel behavior, reveal unexpected features of EC phenotype under different FSS conditions, and identify CDK2 as a key element within the EC regulatory network that governs artery remodeling.

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Section: Introductionmentioning

confidence: 99%

cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling

Deng,

Rukhlendo,

Joshi

et al. 2023

Preprint

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Plxnd1-mediated mechanosensing of blood flow controls the caliber of the Dorsal Aorta via the transcription factor Klf2

He,

Blazeski,

Nilanthi

et al. 2024

Preprint

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The cardiovascular system generates and responds to mechanical forces. The heartbeat pumps blood through a network of vascular tubes, which adjust their caliber in response to the hemodynamic environment. However, how endothelial cells in the developing vascular system integrate inputs from circulatory forces into signaling pathways to define vessel caliber is poorly understood. Using vertebrate embryos and in vitro-assembled microvascular networks of human endothelial cells as models, flow and genetic manipulations, and custom software, we reveal that Plexin-D1, an endothelial Semaphorin receptor critical for angiogenic guidance, employs its mechanosensing activity to serve as a crucial positive regulator of the Dorsal Aorta's (DA) caliber. We also uncover that the flow-responsive transcription factor KLF2 acts as a paramount mechanosensitive effector of Plexin-D1 that enlarges endothelial cells to widen the vessel. These findings illuminate the molecular and cellular mechanisms orchestrating the interplay between cardiovascular development and hemodynamic forces.

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Endothelial mechanosensing: A forgotten target to treat vascular remodeling in hypertension?

Cited by 2 publications

References 133 publications

cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling

cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling

Plxnd1-mediated mechanosensing of blood flow controls the caliber of the Dorsal Aorta via the transcription factor Klf2

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