ArticleThe Journal of clinical investigation2021
Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 58 citations in OpenAlex.
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- The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.Cell communication and signaling : CCS · 2026Review
- Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases.Nature communications · 2026Article
- Podocyte-specific deletion of mechanochannel Piezo1 exacerbates proteinuria and podocyte injury in mouse hypertensive nephropathy.Hypertension research : official journal of the Japanese Society of Hypertension · 2026Article
- Cocrystal-inspired glycyrrhizic acid-azole nanoassemblies for synergistic biofilm disruption and immune modulation in fungal infections.Journal of nanobiotechnology · 2026Article
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- Multitrait analyses identify genetic variants associated with aortic valve function and aortic stenosis risk.Nature genetics · 2026Article
- ClC-3 mediates angiotensin II-induced endothelial dysfunction by inhibiting Akt-Hsp90-eNOS signaling pathway.Frontiers in pharmacology · 2026Article
- Complexed Linalool with Beta-Cyclodextrin Improve Antihypertensive Activity: Pharmacokinetic and Pharmacodynamic Insights.Pharmaceuticals (Basel, Switzerland) · 2025Article
- MSCs ameliorates hyperglycemia-induced endothelial injury through modulation of mitochondrial dynamics.Cell death & disease · 2025Article
- PIEZO Force Sensing in Vascular Biology: An Explosion of New Knowledge, Concepts and Opportunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
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- Mechanism of Sangqi Qingxuan Liquid in Alleviating Vascular Endothelial Injury in Hypertension Focuses on β-Catenin.Chinese journal of integrative medicine · 2025Article
- The pro-aging and rejuvenating effects of young and aged perivascular adipose tissues on endothelial function and inflammation.Biogerontology · 2025Article
- Phosphorylation of endothelial histone H3.3 serine 31 by PKN1 links flow-induced signaling to proatherogenic gene expression.Nature cardiovascular research · 2025Article
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9 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Formation of NO by endothelial NOS (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation, and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and induce the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and Gq/G11-mediated signaling, as well as by Ca2+ and phosphoinositide-dependent protein kinase 1 (PDK1), plays a pivotal role in this process. Active PKN2 promoted the phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved the phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation, whereas active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone, and blood pressure.
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