TY - JOUR
T1 - Endothelial cell Piezo1 promotes vascular smooth muscle cell differentiation on large arteries
AU - Abello, Javier
AU - Yin, Ying
AU - Zhao, Yonghui
AU - Maurer, Josh
AU - Lee, Jihui
AU - Bodell, Cherokee
AU - Richee, Jahmiera
AU - Clevenger, Abigail J.
AU - Burton, Zarek
AU - Goeckel, Megan E.
AU - Lin, Michelle
AU - Grainger, Stephanie
AU - Halabi, Carmen M.
AU - Raghavan, Shreya A.
AU - Sah, Rajan
AU - Stratman, Amber N.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2025/3
Y1 - 2025/3
N2 - Vascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulating klf2a, a blood flow responsive transcription factor, expression levels and altered targeting of vSMCs between arteries and veins. Increasing Piezo1 activity suppressed klf2a and increased vSMC association with the cardinal vein, while inhibition of Piezo1 activity increased klf2a levels and decreased vSMC association with arteries. We supported the small molecule findings with in vivo genetic suppression of piezo1 and 2 in zebrafish, resulting in loss of transgelin+ vSMCs on the dorsal aorta. Further, endothelial cell (EC)-specific Piezo1 knockout in mice was sufficient to decrease vSMC accumulation along the descending dorsal aorta during development, thus phenocopying our zebrafish data, and supporting functional conservation of Piezo1 in mammals. To determine the underlying mechanism, we used in vitro modeling assays to demonstrate that differential sensing of pulsatile versus laminar flow forces across endothelial cells changes the expression of mural cell differentiation genes. Together, our findings suggest a crucial role for EC Piezo1 in sensing force within large arteries to mediate mural cell differentiation and stabilization of the arterial vasculature.
AB - Vascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulating klf2a, a blood flow responsive transcription factor, expression levels and altered targeting of vSMCs between arteries and veins. Increasing Piezo1 activity suppressed klf2a and increased vSMC association with the cardinal vein, while inhibition of Piezo1 activity increased klf2a levels and decreased vSMC association with arteries. We supported the small molecule findings with in vivo genetic suppression of piezo1 and 2 in zebrafish, resulting in loss of transgelin+ vSMCs on the dorsal aorta. Further, endothelial cell (EC)-specific Piezo1 knockout in mice was sufficient to decrease vSMC accumulation along the descending dorsal aorta during development, thus phenocopying our zebrafish data, and supporting functional conservation of Piezo1 in mammals. To determine the underlying mechanism, we used in vitro modeling assays to demonstrate that differential sensing of pulsatile versus laminar flow forces across endothelial cells changes the expression of mural cell differentiation genes. Together, our findings suggest a crucial role for EC Piezo1 in sensing force within large arteries to mediate mural cell differentiation and stabilization of the arterial vasculature.
KW - Arterial stabilization
KW - Mural cell
KW - Piezo1
KW - Vascular smooth muscle
KW - Zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85212928607&partnerID=8YFLogxK
U2 - 10.1016/j.ejcb.2024.151473
DO - 10.1016/j.ejcb.2024.151473
M3 - Article
C2 - 39729736
AN - SCOPUS:85212928607
SN - 0171-9335
VL - 104
JO - European journal of cell biology
JF - European journal of cell biology
IS - 1
M1 - 151473
ER -