Reactome | High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

Stable Identifier

R-HSA-9856530

DOI

10.3180/R-HSA-9856530.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

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Laminar shear stress produced by high fluid flow across endothelial cells causes the cells to produce vasodilatory nitric oxide (NO) and to elongate from polygonal to ellipsoid such that their long axes become parallel with direction of the flow (Nerem et al. 1981, Dewey et al. 1981, reviewed in Tamargo et al. 2023). Nitric oxide produced by endothelial cells modulates soluble guanylyl cyclase and cGMP-dependent kinase in surrounding smooth muscle cells to cause vasodilation (reviewed in Feletou et al. 2008, 2012). By optimizing blood flow without inflammation, the response to laminar shear stress is atheroprotective.
Laminar shear stress on endothelial cells is detected by the glycocalyx, caveolae, cilia, the mechanosensitive ion channel PIEZO1 located on the apex of the cell, and the PECAM1:CDH5:KDR (PECAM1:VE-cadherin:VEGFR2) complex located on the lateral surfaces between adjacent cells (reviewed in Tanaka et al. 2021). The active molecular components, mechanisms of activation, and downstream events related to the glycocalyx, caveolae, and cilia are incompletely characterized so the annotation here focuses more on PIEZO1 and the PECAM1:CDH5:KDR complex.
The force of the flow on the membrane of the endothelial cell activates the mechanosensitive ion channel PIEZO1 and, indirectly, the ion channel TRPV4 to transport cations, notably calcium, from the extracellular region to the cytosol (reviewed in Li et al. 2014, Ranade et al. 2014, Fang et al. 2021, Xiao et al. 2023). Cytosolic calcium activates the protease complex Calpain2 to cleave the cytoskeletal proteins TALIN1 and VINCULIN, resulting in changes to the cytoskeleton that alter the shape of the endothelial cell (Miyazaki et al. 2007).
Flow-sensitive potassium channels (which may include Kir2.1 and TREK1) and chloride channels (which may include LRRC8A) are also observed to open, however their mechanisms of activation and downstream events are incompletely characterized (reviewed in Tanaka et al. 2021).
Cytosolic calcium activates Pannexin channels to release ATP (Wang et al. 2016), which binds the P2RY2 (P2Y2) receptor on the cell surface in an autocrine and paracrine manner and thereby activates Galpha(q/11)-PI3K-AKT1 signaling. Both signaling by P2RY2 and signaling by a mechanosensitive complex containing PECAM1 and KDR (VEGFR2) (inferred from mouse homologs in Tzima et al. 2005) produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which binds AKT1 and enhances the phosphorylation of AKT1 on serine-475 by the mTORC2 complex.
Through a PI3K-independent mechanism, P2RY2 signaling and cytosolic calcium activate the kinase PDPK1, which phosphorylates the kinase PKN2 (PRK2) (Jin et al. 2021). Phospho-PKN2 then phosphorylates AKT1 on threonine-308 (Jin et al. 2021). Phospho-T308,S475-AKT1 phosphorylates serine-1177 of NOS3 (eNOS) while phospho-PKN2 also phosphorylates serine-1179 of NOS3 (Jin et al. 2021), causing increased nitric oxide production (reviewed in Cabou and Martinez 2022).
Laminar shear stress increases secretion of Adrenomedullin (ADM), a vasodilator, by endothelial cells through an uncharacterized mechanism (Iring et al. 2019). ADM binds the AM1 receptor and signals through G-alpha(s), adenylate cyclase, and resultant cAMP to activate protein kinase A (PKA) to phosphorylate serine-633 of NOS3, further increasing nitric oxide production (Iring et al. 2019).
The sphingosine 1-phosphate receptor S1PR1, which couples to Galpha(i1) and Galpha(i3), contributes in a ligand-independent manner to activation of AKT and NOS3, however the intermediate steps are incompletely characterized (reviewed in Tanaka et al. 2021). Other GPCRs such as GPR68 also become activated, possibly through flow-induced deformation of the extracellular domain (reviewed in Tanaka et al. 2021).

Literature References

PubMed ID	Title	Journal	Year
35682562	The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology Martinez, LO, Cabou, C	Int J Mol Sci	2022
7278195	Vascular endothelial morphology as an indicator of the pattern of blood flow Levesque, MJ, Cornhill, JF, Nerem, RM	J Biomech Eng	1981
33543538	Early events in endothelial flow sensing Joshi, D, Timalsina, S, Tanaka, K, Schwartz, MA	Cytoskeleton (Hoboken)	2021
24958852	Piezo1, a mechanically activated ion channel, is required for vascular development in mice Qiu, Z, Ranade, SS, Murthy, SE, Li, YS, Bandell, M, Coste, B, Cahalan, SM, Woo, SH, Patapoutian, A, Chien, S, Hur, SS, Mathur, J, Xu, J	Proc Natl Acad Sci U S A	2014
33422128	Structure, kinetic properties and biological function of mechanosensitive Piezo channels Fang, XZ, Xu, JQ, Gao, XH, Pan, SW, Shang, Y, Zhou, T, Peng, ZK, Xiong, W, Wang, YX, Sun, MM, He, YJ	Cell Biosci	2021
7278196	The dynamic response of vascular endothelial cells to fluid shear stress Dewey, CF, Davies, PF, Bussolari, SR, Gimbrone, MA	J Biomech Eng	1981
27797339	Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release Offermanns, S, Wettschureck, N, Chennupati, R, Kaur, H, Iring, A, Wang, S	J Clin Invest	2016
37595342	Mechanosensitive GPCRs and ion channels in shear stress sensing Liu, J, Xu, XZS, Xiao, R	Curr Opin Cell Biol	2023
37225873	Flow-induced reprogramming of endothelial cells in atherosclerosis Jo, H, Tamargo, IA, Park, C, Kim, Y, Baek, KI	Nat Rev Cardiol	2023
17596297	Requirement of Ca2+ influx- and phosphatidylinositol 3-kinase-mediated m-calpain activity for shear stress-induced endothelial cell polarity Ohata, H, Honda, K, Miyazaki, T	Am J Physiol Cell Physiol	2007
25119035	Piezo1 integration of vascular architecture with physiological force Cubbon, RM, Hou, B, Bilton, J, Ajuh, P, Kearney, MT, Beech, DJ, Prasad, RK, Carter, DA, Ludlow, MJ, Tumova, S, Bruns, A, Majeed, Y, Kim, HR, Evans, PC, Wilson, LA, Ainscough, JF, Rode, B, Fu, Z, McKeown, L, Hyman, AJ, Sedo, A, Imrie, H, Yuldasheva, NY, Bailey, MA, Young, RS, Muraki, K, Li, J, Dear, TN	Nature	2014