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-Ca 2+ 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: hypoxia, pulmonary hypertension, genetics. In the autumn of 2015 at the Lost Valley Ranch in Sedalia, Colorado, the 34th Grover Conference, on pulmonary circulation in the "omics" era, convened for a 4-day symposium to discuss contemporary scientific concepts in the genetics, genomics, proteomics, and epigenetics of pulmonary vascular diseases. This biannual meeting, sponsored by the American Thoracic Society and co-led this year by Drs. C. Gregory Elliot, Wendy K. Chung, D. Hunter Best, and Eric D. Austin, commemorates the perpetual and transformative scientific contributions of Dr. Robert Grover 1 to the fields of high-altitude medicine and pulmonary vascular disease. This review is part of an ongoing Pulmonary Circulation thematic series that aims to provide a synopsis of key concepts presented at this year's Grover Conference.Here, we summarize the discussions that constituted a section of the conference emphasizing novel genetic and molecular mechanisms underpinning "pulmonary vascular and ventricular dysfunction in the susceptible patient." To accomplish this, three concepts are reviewed in detail: the functional relevance of chronic hypoxia (CH), discovered through genomic analyses; novel molecular mechanisms and phenotypic signatures of pulmonary vascular disease in sickle cell disease; and hormonal regulation of vascular f...

IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells

“…In addition, it has been shown that myocardial pressure overload from hypertension can induce IL-33 production by cardiovascular endothelial cells [ 26 ], which may induce local or even systemic inflammation. Here, exposure of WT mice to hypoxia induced obvious right, but not left ventricular hypertrophy as verified by alterations in single cardiomyocyte diameter, while knockdown of St2 significantly abrogated this phenomenon, clearly implicating the IL-33/ST2 axis in the pathogenesis of HPH and consequent right heart failure.There are already several studies in the literature implicating HIF-1α and VEGF in the pathogenesis of the vascular remodelling which results in HPH [ 1 , 2 ]. Increased expression of HIF-1α has been noted in the serum of patients with HPH and in the lungs in animal models [ 10 ].…”

“…Hypoxic pulmonary hypertension (HPH) is commonly observed in the context of chronic hypoxia caused by a variety of lung diseases [ 1 , 2 ]. Although the precise mechanisms of HPH are largely unknown, hypoxia enhanced pulmonary vasoconstriction and vascular remodelling are considered to be the two major pathogenic processes of HPH, resulting in elevated pulmonary vascular resistance and consequent pulmonary artery pressure with eventual cardiac hypertrophy and failure.…”

“…It is therefore reasonable to hypothesize that IL-33 also contributes to the vascular remodelling processes of HPH through actions on vascular endothelial cells. In addition, vascular endothelial cell growth factor (VEGF) is a key “end effector” molecule in the vascular remodelling of HPH, which promotes angiogenesis by regulating the proliferation, migration and differentiation of endothelial cells [ [1] , [2] , [3] ]. The expression of VEGF is in turn regulated by the “molecular switch” molecule hypoxia-induced factor 1-alpha (HIF-1α) [ 10 , 11 ].…”

Transcriptomic Signature of Right Ventricular Failure in Experimental Pulmonary Arterial Hypertension: Deep Sequencing Demonstrates Mitochondrial, Fibrotic, Inflammatory and Angiogenic Abnormalities

“…Polypeptide N -acetyl-galactose-aminyl-transferase 13 ( Galnt13 ) was also downregulated (−2.7-fold). Galnt is also downregulated in the blood of sickle-cell disease patients with pulmonary hypertension and could distinguish patients with and without increased RVSP with 100% accuracy [ 64 ]. Moreover, genetic association comparing patients with normal versus elevated tricuspid regurgitation jet velocity and pulmonary hypertension revealed 5 single nucleotide polymorphisms within this gene [ 64 ].…”

Ethnicity in Pulmonary Arterial Hypertension

“…44 Work evaluating the pathobiology of people living at high altitude provides insight into the role of genetic variation and response to hypoxia. 45 Novel research suggests that adverse perinatal events, including pre-eclampsia or periods of fetal hypoxia, could trigger a cascade of epigenetic events conferring a risk of subsequent pulmonary vascular disease. 46 This line of research is interesting and relevant, because there are known racial disparities in neonatal and perinatal mortality.…”