Hypoxia‐induced pulmonary hypertension—Utilizing experiments of nature

Abstract

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest in understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature, specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather than cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation. K E Y W O R D S genetics, high-altitude, hypoxia-inducible factor, hypoxiainducible factor prolyl hydroxylase 2, oxygen sensing, pulmonary vasoconstriction, vascular remodelling 1 | INTRODUCTION Under physiological conditions, the adult pulmonary circulation is maintained as a high-flow, low-pressure, and low-resistance system through which the entire cardiac output (CO) must pass. Exposure to hypoxia leads to the constriction of small resistance arteries in the lung, referred to as hypoxic pulmonary vasoconstriction (HPV)

Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders

“…There is compelling evidence from experimental models implicating the HIF pathway in hypoxic pulmonary hypertension [243,244]. Importantly, pulmonary circulation abnormalities associated with the impaired HIF signaling have been recapitulated in genetically modified mice.…”

Hsa_circ_0002062 Promotes the Proliferation of Pulmonary Artery Smooth Muscle Cells by Regulating the Hsa-miR-942-5p/CDK6 Signaling Pathway

“…Despite the application of recent advances in the treatment of HPH, patients with this disease experience a poor median survival rate ( Li et al, 2019 ). Hitherto, many signaling cascades have been detected to play a role in HPH and hold great promise as potentially useful targets for therapeutic intervention ( Gassmann et al, 2020 ). Nevertheless, treatment options remain limited, and in-depth elucidation of the detailed molecular mechanisms underlying vascular remodeling in HPH is urgently required ( Smith et al, 2020 ).…”

Enhanced Vasoconstriction Mediated by α1-Adrenergic Mechanisms in Small Femoral Arteries in Newborn Llama and Sheep Gestated at Low and High Altitudes

“…Regarding increased R MAX for K + observed in animals with chronic exposure like NBLL at HA, there are no previous studies published on the effect of hypobaric hypoxia on femoral vessels in the NBLL. Exposure of rats to hypoxia of 10% by 24 h and 48 h decreases the contractile response in aorta rings (Auer and Ward, 1998 ), while pulmonary arterial bed hypoxia promotes vasoconstriction, upregulation of voltage-dependent Ca 2+ channels, and a hyperplasic/hypertrophic structural remodeling related with increased R MAX (Wan et al, 2013 ; Dunham-Snary et al, 2017 ; Reyes et al, 2018 ; Gassmann et al, 2021 ). Other mechanisms such as increased Ca 2+ sensitization in vascular smooth muscle can also increase R MAX (Jernigan and Resta, 2014 ).…”