Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality

TLDR

Sepsis is a leading cause of morbidity and mortality, with its pathophysiology thought to involve complex interactions between inflammatory and coagulation mediators. The study aims to clarify the role of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in sepsis to inform new therapeutic strategies. Using animal and human sepsis models, the authors measured circulating VEGF/PlGF and manipulated their signaling via adenovirus‑mediated soluble Flt‑1 overexpression and receptor‑targeting antibodies. Soluble Flt‑1 overexpression and Flk‑1 blockade reduced VEGF/PlGF levels, improved cardiac function, decreased vascular permeability, and lowered mortality, while VEGF overexpression worsened outcomes, confirming VEGF’s pathogenic role in sepsis.

Abstract

Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus–sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.