Pathophysiology of endotoxin: microvascular dysfunction, and the roles of VEGF and nitric oxide (NO)

Abstract

Vascular endothelial growth factor (VEGF) elicits nitric oxide (NO)-dependent vasodilation and plays major roles in angiogenesis and wound healing. Although bacterial endotoxin (LPS) has been shown to alter endothelial NO synthase (ecNOS)/NO regulation, interactive effects of LPS and NO-dependent responses to VEGF have not been examined. We compared microvascular endothelium-dependent relaxation (EDR) to VEGF¹⁶⁵ (10⁻¹⁴- 3x10⁻¹¹M) in mesenteric microvessels (~150 [æ]m) isolated from control (sterile saline-treated) and endotoxemic (E. coli LPS; 4 mg/kg i.p., 16 hrs) guinea pigs. Specialized microvessel myographs and isometric techniques were used to study EDR to VEGF following pre-contraction of vessels with endothelin-1 (~EC₅₀). Microvessels isolated from control animals, but not LPS-treated animals, exhibited significant concentration-dependent EDR to VEGF; vasorelaxation (% endothelin precontraction) at 3x10⁻¹¹ M VEGF averaged 63±17% and 8.1±9.9%, respectively. Furthermore, exposure to the NO synthase inhibitor L-NMMA (100[æ]M) significantly blocked vasorelaxation to VEGF (<3x10⁻¹¹ M) of control microvessels, but produced no effect on microvessels from LPS-treated animals; relaxation at 10⁻¹¹ M VEGF averaged 4.4±18% and -11±11%, respectively. Thus, these data indicate that in vivo endotoxemia impairs NO-dependent in vitro microvascular relaxation to VEGF. Since NO plays a major role in VEGF-stimulated vasodilation, permeability, proliferation, and angiogenesis, these data may implicate LPS-induced impairment of VEGF-stimulated NO production in the endothelial pathophysiology of shock/sepsis.