Journal article
Vascular endothelial cell morphology and alignment regulate VEGF-induced endothelial nitric oxide synthase activation
Cytoskeleton (Hoboken, N.J.), v 81(9-10), pp 473-487
22 May 2024
PMID: 38775643
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) inhibits platelet and leukocyte adhesion while promoting vasorelaxation in smooth muscle cells. Dysfunctional regulation of eNOS is a hallmark of various vascular pathologies, notably atherosclerosis, often associated with areas of low shear stress on endothelial cells (ECs). While the link between EC morphology and local hemodynamics is acknowledged, the specific impact of EC morphology on eNOS regulation remains unclear. Morphological differences between elongated, aligned ECs and polygonal, randomly oriented ECs correspond to variations in focal adhesion and cytoskeletal organization, suggesting differing levels of cytoskeletal prestress. However, the functional outcomes of cytoskeletal prestress, particularly in the absence of shear stress, are not extensively studied in ECs. Some evidence suggests that elongated ECs exhibit decreased immunogenicity and enhanced NO production. This study aims to elucidate the signaling pathways governing VEGF-stimulated eNOS regulation in the aligned EC phenotype characterized by elongated and aligned cells within a monolayer. Using anisotropic topographic cues, bovine aortic endothelial cells (BAECs) were elongated and aligned, followed by VEGF treatment in the presence or absence of cytoskeletal tension inhibitors. Phosphorylation of eNOS ser1179, AKT ser437 and FAK Tyr397 in response to VEGF challenge were significantly heightened in aligned ECs compared to unaligned ECs. Moreover this response proved to be robustly tied to cytoskeletal tension as evinced by the abrogation of responses in the presence of the myosin II ATPase inhibitor, blebbistatin. Notably, this work demonstrates for the first time the reliance on FAK phosphorylation in VEGF-mediated eNOS activation and the comparatively greater contribution of the cytoskeletal machinery in propagating VEGF-eNOS signaling in aligned and elongated ECs. This research underscores the importance of utilizing appropriate vascular models in drug development and sheds light on potential mechanisms underlying vascular function and pathology that can help inform vascular graft design.
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Details
- Title
- Vascular endothelial cell morphology and alignment regulate VEGF-induced endothelial nitric oxide synthase activation
- Creators
- Aparna Bhattacharyya - Drexel University, School of Biomedical Engineering, Science, and Health SystemsKenneth A. Barbee - Drexel University, School of Biomedical Engineering, Science, and Health Systems
- Publication Details
- Cytoskeleton (Hoboken, N.J.), v 81(9-10), pp 473-487
- Publisher
- Wiley
- Number of pages
- 15
- Grant note
- U01HL116256 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) National Heart, Lung and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:001228985800001
- Scopus ID
- 2-s2.0-85193782838
- Other Identifier
- 991021880395404721
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- Web of Science research areas
- Cell Biology