2. Academic Validation
  3. Piezo1 activates nitric oxide synthase in red blood cells via protein kinase C with increased activity in diabetes

Piezo1 activates nitric oxide synthase in red blood cells via protein kinase C with increased activity in diabetes

  • Mechanobiol Med. 2025 Jul 28;3(3):100145. doi: 10.1016/j.mbm.2025.100145.
Gurneet S Sangha 1,  Lauren V Smith 1,  Marzyeh Kheradmand 1,  Kashif M Munir 2,  Nimisha Rangachar 1,  Callie M Weber 1,  Zohreh Safari 3,  Stephen C Rogers 3,  Allan Doctor 3,  Alisa Morss Clyne 1
Affiliations

Affiliations

  • 1 Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Dr, College Park, MD, 20742, USA.
  • 2 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 800 Linden Avenue, Baltimore, MD, 21201, USA.
  • 3 Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD, 21201, USA.
PMID: 40809083 DOI: 10.1016/j.mbm.2025.100145
Abstract

Nitric oxide (NO) is a key signaling molecule in maintaining cardiovascular health. While endothelial cells were initially thought to exclusively contain endothelial nitric oxide synthase (eNOS), an enzyme that produces NO, recent evidence suggests that red blood cells (RBC) also contain functional eNOS that impacts cardiovascular function. However, the mechanisms driving RBC eNOS activation are not well understood. Like endothelial cells, RBC are mechanosensitive via the stretch-activated piezo1 CA2+ channel. Therefore, we investigated how piezo1 stimulation induced RBC and endothelial eNOS phosphorylation. We further examined how this mechanism is affected during diabetes, a condition known to impair vascular NO bioavailability. Our results reveal that piezo1 stimulation activated RBC eNOS via protein kinase C (PKC) and endothelial eNOS partially via protein kinase B (Akt). Surprisingly, piezo1-stimulation increased eNOS phosphorylation at the Ser1177 activation site nearly 20-fold in RBC from diabetic patients compared to 5.5-fold in RBC from non-diabetic patients. These findings highlight important differences in eNOS activation between RBC and endothelial cells and suggest potential biomolecular markers for targeting vascular NO bioavailability in health and disease.

Keywords

Diabetes; Mechanobiology; Nitric oxide; Piezo1; Protein kinase c; Red blood cells.

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