Tissue Factor Pathway Inhibitor Overexpression Inhibits Hypoxia-Induced Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a commonly recognized complication of chronic respiratory disease. Enhanced vasoconstriction, pulmonary vascular remodeling, and in situ thrombosis contribute to the increased pulmonary vascular resistance observed in PH associated with hypoxic lung disease. The tissue factor pathway regulates fibrin deposition in response to acute and chronic vascular injury. We hypothesized that inhibition of the tissue factor pathway would result in attenuation of pathophysiologic parameters typically associated with hypoxia-induced PH. We tested this hypothesis using a chronic hypoxia-induced murine model of PH using mice that overexpress tissue factor pathway inhibitor (TFPI) via the smooth muscle-specific promoter SM22 (TFPI SM22 ). TFPI SM22 mice have increased pulmonary TFPI expression compared with wild-type (WT) mice. In WT mice, exposure to chronic hypoxia (28 d at 10% O 2 ) resulted in increased systolic right ventricular and mean pulmonary arterial pressures, changes that were significantly reduced in TFPI SM22 mice. Chronic hypoxia also resulted in significant pulmonary vascular muscularization in WT mice, which was significantly reduced in TFPI SM22 mice. Given the pleiotropic effects of TFPI, autocrine and paracrine mechanisms for these hemodynamic effects were considered. TFPI SM22 mice had less pulmonary fibrin deposition than WT mice at 3 days after exposure to hypoxia, which is consistent with the antithrombotic effects of TFPI. Additionally, TFPI SM22 mice had a significant reduction in the number of proliferating (proliferating cell nuclear antigen positive) pulmonary vascular smooth muscle cells compared with WT mice, which is consistent with in vitro findings. These findings demonstrate that overexpression of TFPI results in improved hemodynamic performance and reduced pulmonary vascular remodeling in a murine model of hypoxia-induced PH. This improvement is in part due to the autocrine and paracrine effects of TFPI overexpression.

Thrombin Has Biphasic Effects on the Nitric Oxide-cGMP Pathway in Endothelial Cells and Contributes to Experimental Pulmonary Hypertension

“…A mouse overexpressing tissue factor pathway inhibitor (TFPI) was found to have reduced pulmonary hypertension when exposed to hypoxia [50]. We have recently shown that pharmacological inhibition of FXa by the direct, selective inhibitor rivaroxaban is beneficial in the MCT model of experimental pulmonary hypertension [6].…”

Tissue factor pathway inhibitor: structure-function

“…Heterozygous mTFPI ΔK1 deficiency also increases neointimal proliferation in the murine model of flow cessation-induced vascular remodeling (170). On the other hand, over expression of mTFPIα (the isoform only present in the platelets of adult mice) in vascular smooth muscle cells limits ferric chloride induced carotid artery occlusion (171), reduces the smooth muscle cell proliferation and pulmonary vascular remodeling induced by chronic hypoxia (172), and unexpectedly lowers plasma cholesterol levels and atherosclerotic plaque development in the apoE knock-out model of atherosclerosis (173). …”

Tissue Factor Pathway Inhibitor Blocks Angiogenesis via Its Carboxyl Terminus

“…TFPI expression is increased locally in vascular smooth muscle cells, but also at the endothelial surface, as evidenced by increased heparin-releasable TFPI and systemically, with raised plasma TFPI antigen levels. 18 Heparin-releasable TFPI must come from the intravascular, endothelial surface. We demonstrated a clear inhibition of angiogenesis in recovery from hind-limb ischemia in these mice.…”

“…17 These mice (in C57Bl/6 background) have increased vascular expression of full-length murine TFPI. 18 Male, age-matched C57Bl/6 mice were used as controls in all experiments.…”