HO Sensitivity of K Channels in Hypoxic Pulmonary Vasoconstriction: Experimental Conditions Matter.

Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange but, when impaired, can result in life-threatening hypoxemia. Moreover, under conditions of generalized alveolar hypoxia, HPV can result in pulmonary hypertension. Voltage-gated K channels (K channels) are key to HPV: a change in the intracellular hydrogen peroxide (HO) levels during acute hypoxia is assumed to modulate these channels' activity to trigger HPV.

Piezo1 in PASMCs: Critical for Hypoxia-Induced Pulmonary Hypertension Development.

Background: Pulmonary hypertension (PH) is a life-threatening and progressive yet incurable disease. The hallmarks of PH comprise (1) sustained contraction and (2) excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). A major stimulus to which PASMCs are exposed during PH development is altered mechanical stress, originating from increased blood pressure, changes in blood flow velocity, and a progressive stiffening of pulmonary arteries.

Use of FRET-Sensor 'Mermaid' to Detect Subtle Changes in Membrane Potential of Primary Mouse PASMCs.

Subtle changes in the membrane potential of pulmonary arterial smooth muscle cells (PASMCs) are pivotal for controlling pulmonary vascular tone, e.g., for initiating Hypoxic Pulmonary Vasoconstriction, a vital mechanism of the pulmonary circulation.

Deletion of classical transient receptor potential 1, 3 and 6 alters pulmonary vasoconstriction in chronic hypoxia-induced pulmonary hypertension in mice.

Chronic hypoxia-induced pulmonary hypertension (CHPH) is a severe disease that is characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling. The resulting increase in pulmonary vascular resistance (PVR) causes right ventricular hypertrophy and ultimately right heart failure. In addition, increased PVR can also be a consequence of hypoxic pulmonary vasoconstriction (HPV) under generalized hypoxia.

Mitochondrial oxygen sensing of acute hypoxia in specialized cells - Is there a unifying mechanism?

Acclimation to acute hypoxia through cardiorespiratory responses is mediated by specialized cells in the carotid body and pulmonary vasculature to optimize systemic arterial oxygenation and thus oxygen supply to the tissues. Acute oxygen sensing by these cells triggers hyperventilation and hypoxic pulmonary vasoconstriction which limits pulmonary blood flow through areas of low alveolar oxygen content. Oxygen sensing of acute hypoxia by specialized cells thus is a fundamental pre-requisite for aerobic life and maintains systemic oxygen supply.

Experimental Setup for Investigation of Acute Mitochondrial Oxygen Sensing in Primary Cells.

The ability to sense and respond to acute changes in oxygen is essential for the viability of cells and organisms. To study molecular mechanisms of acute oxygen sensing, we established a setup for the adjustment of acute hypoxic conditions in cultured cells, exemplified here for the use of primary pulmonary arterial smooth muscle cells (PASMCs). The mitochondrial electron transport chain (ETC) is the main consumer of oxygen but recently also emerged as essential oxygen sensor suggesting that the ETC itself adapts its electron flux to oxygen availability.

SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH can be caused by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMCs) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVECs). On reexposure to normoxia, chronic hypoxia-induced PH in mice is reversible.

A Microfluidic System for Simultaneous Raman Spectroscopy, Patch-Clamp Electrophysiology, and Live-Cell Imaging to Study Key Cellular Events of Single Living Cells in Response to Acute Hypoxia.

The ability to sense changes in oxygen availability is fundamentally important for the survival of all aerobic organisms. However, cellular oxygen sensing mechanisms and pathologies remain incompletely understood and studies of acute oxygen sensing, in particular, have produced inconsistent results. Current methods cannot simultaneously measure the key cellular events in acute hypoxia (i.

Enhanced Shear Force Responsiveness of Epithelial Na Channel's (ENaC) δ Subunit Following the Insertion of N-Glycosylation Motifs Relies on the Extracellular Matrix.

Members of the Degenerin/epithelial Na channel (ENaC) protein family and the extracellular cell matrix (ECM) form a mechanosensitive complex. A core feature of this complex are tethers, which connect the channel with the ECM, however, knowledge about the nature of these tethers is scarce. N-glycans of α ENaC were recently identified as potential tethers but whether N-glycans serve as a ubiquitous feature for mechanosensation processes remains unresolved.

Author Correction: NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and death worldwide. Peroxynitrite, formed from nitric oxide, which is derived from inducible nitric oxide synthase, and superoxide, has been implicated in the development of emphysema, but the source of the superoxide was hitherto not characterized. Here, we identify the non-phagocytic NADPH oxidase organizer 1 (NOXO1) as the superoxide source and an essential driver of smoke-induced emphysema and pulmonary hypertension development in mice.

Cytochrome P450 epoxygenase-derived 5,6-epoxyeicosatrienoic acid relaxes pulmonary arteries in normoxia but promotes sustained pulmonary vasoconstriction in hypoxia.

Aims: The aim of the study was to investigate the role of cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in sustained hypoxic pulmonary vasoconstriction (HPV).

Methods: Vasomotor responses of isolated mouse intrapulmonary arteries (IPAs) were assessed using wire myography. Key findings were verified by haemodynamic measurements in isolated perfused and ventilated mouse lungs.

Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing.

Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited.

Amelioration of elastase-induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice.

Background And Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS mice but also precedes emphysema development.

Shear force sensing of epithelial Na channel (ENaC) relies on -glycosylated asparagines in the palm and knuckle domains of αENaC.

Mechanosensitive ion channels are crucial for normal cell function and facilitate physiological function, such as blood pressure regulation. So far little is known about the molecular mechanisms of how channels sense mechanical force. Canonical vertebrate epithelial Na channel (ENaC) formed by α-, β-, and γ-subunits is a shear force (SF) sensor and a member of the ENaC/degenerin protein family.

Development of a Gas-Tight Microfluidic System for Raman Sensing of Single Pulmonary Arterial Smooth Muscle Cells Under Normoxic/Hypoxic Conditions.

Acute hypoxia changes the redox-state of pulmonary arterial smooth muscle cells (PASMCs). This might influence the activity of redox-sensitive voltage-gated K⁺-channels (Kv-channels) whose inhibition initiates hypoxic pulmonary vasoconstriction (HPV). However, the molecular mechanism of how hypoxia-or the subsequent change in the cellular redox-state-inhibits Kv-channels remains elusive.

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing.

Rationale: Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as a critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and the mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing, remain unresolved.

Gadolinium released by the linear gadolinium-based contrast-agent Gd-DTPA decreases the activity of human epithelial Na channels (ENaCs).

Background: Gadolinium-based-contrast-agents (GBCAs) are used for magnetic-resonance-imaging and associated with renal and cardiovascular adverse reactions caused by released Gd ions. Gd is also a modulator of mechano-gated ion channels, including the epithelial Na channel (ENaC) that is expressed in kidney epithelium and the vasculature. ENaC is important for salt-/water homeostasis and blood pressure regulation and a likely target of released Gd from GBCAs causing the above-mentioned adverse reactions.