Endothelial Function in Sepsis and Critical Illness

Endothelial cells line the microvasculature and form a dynamic barrier that regulates fluid exchange, vascular tone and haemostasis. In sepsis and critical illness, this barrier becomes destabilised by inflammatory mediators, oxidative stress and direct microbial products, leading to increased permeability, tissue oedema and impaired organ perfusion. Disruption of intercellular junctions and degradation of the endothelial glycocalyx further amplify leukocyte adhesion, coagulation abnormalities and microvascular thrombosis. Such perturbations of endothelial function contribute to hypoperfusion, organ dysfunction and the high mortality associated with severe sepsis. Recent work has emphasised the endothelium not merely as a passive victim of systemic inflammation but as an active regulator of both injury and repair, offering novel targets for therapeutic intervention and biomarker development.

Research from Nature Portfolio

Investigations have identified intermedin, a peptide of the calcitonin family, as an endogenous protector of the vascular barrier during sepsis. By promoting the Rab11-dependent recycling of vascular endothelial cadherin to cell–cell contacts, intermedin restores endothelial junction integrity and limits capillary leak. Concurrently, it attenuates macrophage recruitment through downregulation of chemokine receptor expression, thereby moderating the cytokine storm. In experimental models, administration of intermedin reduced organ injury and improved survival, and elevated circulating levels in patients correlated with lower severity scores and better outcomes. This dual action on barrier repair and inflammation highlights intermedin as a promising self-protective factor in sepsis.

Endothelial Function in Sepsis and Critical Illness publication trend

The graph below shows the total number of articles in endothelial function in sepsis and critical illness across all publications each year (not limited to Nature Index journals).

Technical terms

Endothelium: The single layer of cells lining the interior of blood vessels, regulating vascular permeability, tone and blood–tissue exchange.

Glycocalyx: A gel-like mesh of glycoproteins and proteoglycans on the endothelial surface that maintains barrier function and shear-stress sensing.

Angiopoietins: Ligands (notably Ang-1 and Ang-2) that bind the Tie-2 receptor to stabilise (Ang-1) or destabilise (Ang-2) endothelial junctions.

Intermedin: A peptide of the calcitonin family that enhances endothelial junction repair and attenuates inflammatory cell recruitment in sepsis.

DNA-PKcs: The catalytic subunit of DNA-dependent protein kinase involved in DNA repair and, when misdirected, in endothelial actin remodelling during endotoxaemia.

Vascular permeability: The capacity of blood vessel walls to allow fluids and solutes to pass into surrounding tissues, often increased in inflammatory states.

References

1. DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy. Research (2024).
2. Vascular leak in sepsis: physiological basis and potential therapeutic advances. Critical Care (2024).
3. Vascular endothelial cadherin shedding is more severe in sepsis patients with severe acute kidney injury. Critical Care (2019).
4. Intermedin protects against sepsis by concurrently re-establishing the endothelial barrier and alleviating inflammatory responses. Nature Communications (2018).