Abstract 4366774: Liver Angiocrine Myeloid-Derived Growth Factor Protects Against Endothelial Dysfunction in Pulmonary Arterial Hypertension

Abstract

Background: Circulating angiogenic growth factors have been implicated in the pathobiology of pulmonary arterial hypertension (PAH), yet their roles remain incompletely understood. Myeloid-derived growth factor (MYDGF) is a hepatic and myeloid-expressed protein which promotes endothelial repair, suppresses pro-fibrotic TGFβ1 signaling, and inhibits the MAP4K4-NFκB axis, but has not been studied in pulmonary vascular disease. Hypothesis: We hypothesized that MYDGF is deficient or dysfunctional in PAH and that supplementation may protect against inflammatory activation of the pulmonary endothelium. Approach: Using the Sugen-hypoxia (SuHx) rat model, we quantified MYDGF in hepatic and pulmonary tissue via immunohistochemistry (IHC) and immunoblotting. We assessed its spatial localization and relationship to pulmonary endothelial activation. In vitro, we tested whether MYDGF supplementation counteracts inflammatory signaling in human pulmonary arterial endothelial cells (HPAECs) after exposure to pro-inflammatory media. Circulating MYDGF levels were measured in two human PAH cohorts (PHiNE; Brown University and Servetus; University of Washington) using mass spectrometry and SomaLogic aptamer-based proteomics, respectively. Associations between MYDGF and clinical outcomes were evaluated by regression analysis. Results: SuHx rat livers had reduced MYDGF expression by IHC (6.0% vs 10.4%, p=0.001), with localization to endothelial cells. SuHx lungs exhibited increased VCAM1 staining consistent with endothelial activation (p=0.001). In vitro, MYDGF supplementation attenuated pro-inflammatory signaling (VCAM1) in HPAECs. In PHiNE, plasma MYDGF levels trended toward a decrease in PAH (n = 25) vs controls (n = 25) and increased MYDGF levels had a non-significant association with decreased PVR and increased 6MWD. MYDGF was associated with cytoskeletal proteins in PAH patients and endothelial proliferation in controls. In the Servetus cohort (n = 117), high MYDGF was independently associated with increased mortality (p < 0.01) and right ventricular dilation assessed by echocardiography (p<0.005). Conclusion: We present the first evidence that hepatic MYDGF is deficient in experimental and human PAH and associated with inflammatory endothelial activation and adverse outcomes. MYDGF supplementation protected against endothelial inflammatory signaling in vitro. These findings suggest MYDGF may serve as both a biomarker and therapeutic target in pulmonary vascular disease.