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Review Open Access

Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)

  • Authors:
    • Hang Ruan
    • Xiao-Yan Shen
    • Shi-Yan Liu
    • Shu-Sheng Li
  • View Affiliations / Copyright

    Affiliations: Department of Critical‑Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
    Copyright: © Ruan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 87
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    Published online on: February 6, 2026
       https://doi.org/10.3892/ijmm.2026.5758
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Abstract

Sepsis‑induced vasoplegia, a life‑threatening complication of sepsis, has become a focal point of research endeavors aimed at determining its complex mechanisms. However, existing investigations predominantly focus on the role of endothelial cells (ECs) in sepsis, inadvertently dismissing the pivotal contribution of vascular smooth muscle cells (VSMCs). The present review highlights the frequently underappreciated role of VSMCs in sepsis‑induced vasodilation, and provides a comprehensive and systematic elucidation of the associated pathophysiological mechanisms. The current review examines the structural characteristics, localization, phenotypic transitions and heterogeneity of VSMCs, emphasizing their critical role in maintaining vascular homeostasis and regulating blood pressure. Subsequently, the review delves into the multifaceted effects of sepsis on VSMCs. Direct injury to VSMCs in sepsis occurs through pathogens. Additionally, the sepsis‑associated cytokine storm can activate key signaling pathways, such as the NF‑κB and p38 MAPK pathways, leading to a phenotypic shift in VSMCs from a contractile state to a synthetic state, thus enhancing their proliferative and migratory abilities. Concurrently, sepsis disrupts the intricate interaction between ECs and VSMCs, and interferes with calcium homeostasis, ultimately resulting in reduced vascular reactivity and abnormal vascular remodeling. Together, these mechanisms contribute to sepsis‑related vascular dysfunction and multiorgan failure. The in‑depth analysis of these processes in the present review offers novel insights into the pathological mechanisms of sepsis‑induced vasoplegia. The current study also provides a theoretical foundation for the development of clinical intervention strategies targeting VSMCs, with the potential to advance sepsis treatment strategies.

View Figures

Figure 1

VSMCs in physiological and septic
conditions. (A) VSMCs exhibit a quiescent, contractile phenotype
characterized by organized cytoskeletal architecture and intact
regulatory pathways. Key features include: i) Stable anatomical
distribution within the vascular media, maintaining vascular wall
integrity; ii) homogeneous lineage-specific phenotype with minimal
heterogeneity; iii) robust contractility driven by intact calcium
homeostasis and myofilament calcium sensitivity; iv) limited
phenotypic plasticity, with minimal switching from contractile to
synthetic states; v) balanced cellular crosstalk: Intricate
bidirectional interactions with neighboring cells, primarily ECs.
EC-VSMC communication relies on core pathways to maintain vascular
homeostasis, enabling adaptation to mechanical injury, shear stress
and chemical stimuli. (B) Sepsis induces profound structural and
functional perturbations in VSMCs, characterized by five core
changes: i) Altered cellular localization: Disrupted anatomical
distribution within the vascular media due to sepsis-induced cell
injury, compromising vascular wall stability; ii) enhanced cellular
heterogeneity: Expanded phenotypic diversity with an increased
proportion of synthetic VSMCs (arising from lineage switching or
progenitor cell recruitment), contributing to vascular dysfunction;
iii) impaired cellular contractility: Diminished contractile
capacity driven by dysregulated calcium homeostasis and
downregulated contractile proteins; iv) exaggerated cellular
plasticity: Prominent phenotypic switching from contractile to
synthetic states, associated with increased proliferation,
migration and secretion of proinflammatory mediators; v)
dysregulated cellular crosstalk: Collapse of bidirectional EC-VSMC
communication, cytokine secretion becomes proinflammatory
(increased release of proinflammatory cytokines), preventing
adaptation to stressors. The figure was constructed using Figdraw
2.0 tool (https://www.figdraw.com/#/), with
official authorization obtained by the authors (authorization no.:
PTSIYbe897).VSMCs, vascular smooth muscle cells; ECs, endothelial
cells; PO2, partial pressure of oxygen.

Figure 2

Regulation of Ca2+ and
signal transduction in VSMCs. Ca2+ enters VSMCs via
multiple pathways, including VDCC, ROCC, TRPC and SOC.
Intracellular calcium handling relies on the PMCA and NCX at the
cell membrane, as well as organelle-mediated transport in
mitochondria and the endoplasmic reticulum. VSMC contraction is
regulated by two primary mechanisms: Calcium-dependent and
calcium-sensitive pathways. In the calcium-dependent pathway,
increased intracellular Ca2+ forms a complex with CaM,
activating MLCK. This activation enhances Mg2+-ATPase
activity, driving myosin-actin interaction and subsequent cell
contraction. The calcium-sensitive pathway, mainly the Rho/ROCK
pathway, is activated by sepsis-associated stimuli, including
angiotensin II, leptin and mechanical stretch. PKC also modulates
calcium influx by regulating the activity of calcium and potassium
ion channels at the cell membrane. Additionally, miRNAs fine-tune
these regulatory processes, adding another layer of complexity to
calcium homeostasis and smooth muscle function. The figure was
constructed using Figdraw 2.0 tool (https://www.figdraw.com/#/), with official
authorization obtained by the authors (authorization no.:
PPTAA80b0b).α-SMA, α-smooth muscle actin; BKCa, big-conductance
calcium-activated potassium channel; Ca2+, calcium ions;
CaKII, calcium/calmodulin-dependent protein kinase II; CaM,
calmodulin; EPHB4, Eph receptor B4; EFNB, ephrin B; FKBP, FK506
binding proteins; GPCR, G-protein coupled receptors; Kv,
voltage-gated potassium channel; LPS, lipopolysaccharide; MLCK,
myosin light chain kinase; MLCP, MLC phosphatase; miRNA/miR,
microRNA; NCX, sodium-calcium exchanger; p-CPI-17, phosphorylated
protein kinase C-potentiated inhibitor protein-17; p-MLC20,
phosphorylated myosin light chain 20; p-MYPT, phosphorylated myosin
phosphatase target subunit; PKC, protein kinase C; PKM2, pyruvate
kinase M2; PLC, phospholipase C; PMCA, plasmalemmal calcium ATPase;
ROCC, receptor-operated calcium channel; ROCK, Rho-associated
protein kinase; RyR2, ryanodine receptor 2; SOC, store-operated
calcium channel; TRPC, transient receptor potential channel; VDCC,
voltage-dependent calcium channel.

Figure 3

Conceptual overview of the
convergence of endothelial injury, cytokine storm and
Ca2+/NO imbalance in sepsis-induced VSMC dysfunction.
Sepsis (LPS or polymicrobial infection) initiates three
interconnected pathological processes: Endothelial injury, cytokine
storm and Ca2+/NO imbalance, which synergistically drive
VSMC dysfunction and subsequent sepsis-induced vasoplegia.
Collectively, these events result in VSMC hypocontractility,
phenotypic switching and apoptosis, ultimately causing vascular
hyporeactivity and catecholamine resistance in septic vasoplegia.
The figure was constructed using Figdraw 2.0 tool (https://www.figdraw.com/#/), with official
authorization obtained by the authors (authorization no.:
PWSOU68e36).Ca2+, calcium ions; EC, endothelial cell;
eNOS, endothelial NO synthase; iNOS, inducible NO synthase; LPS,
lipopolysaccharide; NO, nitric oxide; ROS, reactive oxygen species;
VSMC, vascular smooth muscle cell.
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Copy and paste a formatted citation
Spandidos Publications style
Ruan H, Shen X, Liu S and Li S: <p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>. Int J Mol Med 57: 87, 2026.
APA
Ruan, H., Shen, X., Liu, S., & Li, S. (2026). <p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>. International Journal of Molecular Medicine, 57, 87. https://doi.org/10.3892/ijmm.2026.5758
MLA
Ruan, H., Shen, X., Liu, S., Li, S."<p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>". International Journal of Molecular Medicine 57.4 (2026): 87.
Chicago
Ruan, H., Shen, X., Liu, S., Li, S."<p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>". International Journal of Molecular Medicine 57, no. 4 (2026): 87. https://doi.org/10.3892/ijmm.2026.5758
Copy and paste a formatted citation
x
Spandidos Publications style
Ruan H, Shen X, Liu S and Li S: <p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>. Int J Mol Med 57: 87, 2026.
APA
Ruan, H., Shen, X., Liu, S., & Li, S. (2026). <p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>. International Journal of Molecular Medicine, 57, 87. https://doi.org/10.3892/ijmm.2026.5758
MLA
Ruan, H., Shen, X., Liu, S., Li, S."<p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>". International Journal of Molecular Medicine 57.4 (2026): 87.
Chicago
Ruan, H., Shen, X., Liu, S., Li, S."<p>Role of vascular smooth muscle cell pathobiology in sepsis‑induced vasoplegia (Review)</p>". International Journal of Molecular Medicine 57, no. 4 (2026): 87. https://doi.org/10.3892/ijmm.2026.5758
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