Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season

Abstract

The role of microparticles (MPs) and cold in high altitude pulmonary hypertension (HAPH) remains unexplored. We investigated the impact of long-term cold exposure on the pulmonary circulation in lowlanders and high-altitude natives and the role of MPs. Pulmonary hemodynamics were evaluated using Doppler echocardiography at the end of the colder and warmer seasons. We further examined the miRNA content of MPs isolated from the study participants and studied their effects on human pulmonary artery smooth muscle (hPASMCs) and endothelial cells (hPAECs). Long-term exposure to cold environment was associated with an enhanced pulmonary artery pressure in highlanders. Plasma levels of CD62E-positive and CD68-positive MPs increased in response to cold in lowlanders and HAPH highlanders. The miRNA-210 expression contained in MPs differentially changed in response to cold in lowlanders and highlanders. MPs isolated from lowlanders and highlanders increased proliferation and reduced apoptosis of hPASMCs. Further, MPs isolated from warm-exposed HAPH highlanders and cold-exposed highlanders exerted the most pronounced effects on VEGF expression in hPAECs. We demonstrated that prolonged exposure to cold is associated with elevated pulmonary artery pressures, which are most pronounced in high-altitude residents. Further, the numbers of circulating MPs are differentially increased in lowlanders and HAPH highlanders during the colder season.

Molecular regulation and therapeutic implications of cell death in pulmonary hypertension

“…Vascular endothelial growth factor (VEGF) is a star molecule that regulates the mitosis and growth state of endothelial cells (ECs) and can induce apoptosis tolerance in ECs through the external pathway of Fas signaling and the intrinsic pathway of the Bcl-2 protein [32,33]. In various PH models, such as hypoxia, fibrosis, thromboembolism, and hypothermia, VEGF-decreased expression levels are closely related to EC apoptosis at the early stage of PH [24,[34][35][36]. However, in the advanced stage, anti-apoptotic PAECs and PASMCs interact with each other by producing excessive growth factors (e.g., TGFβ, FGF2, ET-1) and exosomes through autocrine and paracrine pathways, which further aggravates the proliferation of both [30,37,38].…”