Vascular endothelial growth factor attenuates trauma-induced injury in rats

Abstract

Endothelial dysfunction and loss of nitric oxide (NO) is an integral part of the initiation and maintenance of the inflammatory process such as that occurring in traumatic shock, and is considered responsible for much of the trauma induced microvascular injury. We investigated the effects of a vascular endothelial growth factor (VEGF) in a rat model of traumatic shock. Pentobarbital-anaesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension and a 93% mortality rate with a mean survival time of 108+/-10 min in 14 rats. Accompanying these effects was a significant degree of endothelial dysfunction and a markedly elevated intestinal myeloperoxidase (MPO) activity. Treatment with 125 microg kg(-1) VEGF administered intravenously 18 h pre-trauma, increased survival rate to 67% (P<0.01), and prolonged survival time to 252+/-24 min in 12 rats (P<0.01). VEGF also significantly preserved the endothelium-dependent relaxation to ACh indicating a preservation of endothelium-derived NO. Our results indicate that endothelial dysfunction with its accompanying loss of NO plays an important role in tissue injury associated with trauma, and that preservation of NO is beneficial in traumatic shock. The mechanisms of the protective effect of VEGF in trauma involves preservation of eNOS function and diminished neutrophil accumulation resulting in reduced neutrophil-mediated tissue injury. British Journal of Pharmacology (2000) 129, 71 - 76

Figure 1

Effects of VEGF on mean arterial blood pressure (MABP). Trauma exerts profound effects on MABP. Vehicle treated trauma rats exhibited a significant decrease in MABP. VEGF (125 μg kg⁻¹) significantly improved the MABP of the trauma rats. Data are expressed as MABP in mmHg±s.e.mean. The number to the top left of each symbol is the number of rats in each group. ^*P<0.01 from trauma and vehicle.

Figure 2

(A) Effects of VEGF on survival time following trauma. Data are expressed as mean survival time in minutes±s.e.mean. The numbers at the bottom of the bars are numbers of rats used in each group. All sham trauma rats survived the 300 min observation period. Untreated trauma rats survived only about half as long, whereas VEGF (125 μg kg⁻¹) treated trauma rats exhibited a significantly longer survival time (P<0.01). (B) Effects of VEGF on survival rate for the 5 h observation period following trauma. VEGF (125 μg kg⁻¹) significantly (P<0.01) prolonged survival rate compared to untreated trauma rats. Numbers at the bottom of the bars are numbers of rats survived among those used in each group.

Figure 3

Intestinal myeloperoxidase activity (MPO) expressed as u 100 mg⁻¹ of ileum weight. Trauma resulted in a significant increase in intestinal MPO (P<0.01) which was significantly (P<0.01) attenuated by VEGF (125 μg kg⁻¹). Data are expressed as means±s.e.mean. The numbers at the bottom of the bars are numbers of rats used in each group.

Figure 4

Summary of vasorelaxation responses of isolated rat superior mesenteric artery rings (SMA). Vasodilation was measured in response to the highest concentration of vasodilators: 100 nM ACh, 1 μM A23187, and 100 μM NaNO₂. Trauma resulted in a significant retardation of relaxation to endothelium-dependent vasodilators (i.e., ACh and A23187) (P<0.01) but not to the endothelium-independent vasodilator (NaNO₂). There was no significant dysfunction in the vascular smooth muscle of the SMA in any of the Sham trauma or trauma groups since the responses to NaNO₂ were all normal. Traumatized rats treated with 125 μg kg⁻¹ VEGF 18 h pre-trauma did not develop endothelial dysfunction. Bar heights are the means; brackets indicate ±s.e.mean. The numbers in the parenthesis indicate the number of rings prepared from each experimental group.

Figure 5

Quantification of histological staining of neutrophils (PMNs) in traumatized rats. Trauma resulted in a significant increase of infiltrated PMNs in the intestine. A significant attenuation of the infiltration was seen with the addition of 125 μg kg⁻¹ VEGF (P<0.01). Data are expressed as means±s.e.mean. The numbers at the bottom of the bars are numbers of fields counted in each of the three groups.