Pulmonary vascular and ventricular dysfunction in the susceptible patient (2015 Grover Conference series)

Abstract

Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca²⁺ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.

Keywords: genetics; hypoxia; pulmonary hypertension.

Figure 1

Schematic showing some of the pathways by which hypoxia-inducible factor (HIF) mediates pulmonary arterial smooth muscle changes during chronic hypoxia. ET-1: endothelin 1; TRPCs: transient potential receptors (canonical); ROCK: Rho kinase; NHE1: Na⁺/H⁺ exchanger 1; AQP1: aquaporin 1.

Figure 2

Schematic diagramming mechanisms involved in the development of pulmonary hypertension in sickle cell disease. Abnormalities characteristically observed in sickle cell disease, including hemolytic anemia, hypercoagulability, and inflammation, coupled with individual genetic susceptibility, result in altered expression of a wide panel of genes. Pathways associated with vascular remodeling, including Wnt signaling, calcium signaling, vascular smooth muscle contraction, and cancer pathways, were significantly represented in patients with elevated right systolic pressures, suggesting that these pathways are likely to play a contributory role in the development of pulmonary hypertension (PH).

Figure 3

Hypoxia increases aldosterone (ALDO) synthesis in pulmonary endothelial cells to promote vascular fibrosis and pulmonary hypertension. In pulmonary artery endothelial cells (PAECs), chronic hypoxia induces binding of the transcription factors c-Fos and c-Jun to the activator protein 1 site upstream of the StAR promoter. Increased StAR expression and activity induced by hypoxia increase pulmonary endothelial ALDO production, which, in turn, upregulates expression of (fibrillar) collagen III and the remodeling proteins matrix metalloproteinase 2 (MMP-2) and MMP-9. Hypoxia-aldosterone signaling in PAECs is also associated with induced collagen III synthesis in pulmonary artery smooth muscle cells (PASMCs) in vitro and fibrotic vascular remodeling of distal pulmonary arterioles and pulmonary hypertension in vivo. Fio₂: fraction of inspired oxygen; StAR: steroidogenic acute regulatory protein.