Hypoxic pulmonary vasoconstriction

Abstract

It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.

FIGURE 1

The time course of pulmonary arterial pressure in a cat recorded by Beutner in 1852 (164) (A) and pulmonary arterial and venous (P. Vein) pressures in a dog recorded by Bradford and Dean in 1894 (212) (B). In A, as described by Beutner (164), “AA’ (is) mean pressure level; a-b movement of the bellows (used to ventilate the animal), b-c heart beats after cessation of bellows movement, d-e heart beats with very slow bellows movement.” Note the rise in pulmonary arterial pressure from b to d, when ventilation was stopped, and fall in pressure from d to e, when ventilation was resumed. As described by Bradford and Dean (212), B shows the “effects of asphyxia on the blood pressure in the pulmonary artery and … in the central end of the pulmonary vein. Mercurial manometers were used in both cases. The rise of pressure in the left auricle at the end of asphyxia is well seen, also the temporary rise in the pulmonary artery following the re-establishment of artificial respiration.” Both A and B were digitally traced from the published recordings, resized, and relabeled for clarity of presentation. Neither recording included scales for pressure (ordinate) or time (abscissa).

FIGURE 2

Time course of respiration, carotid arterial pressure (“Pression Carotide”), and pulmonary arterial pressure (“Pr. Pulmonaire”) recorded in a closed-chest spontaneously breathing dog by Plumier in 1904 (1530) (A) and pressures in the left atrium (LA), pulmonary artery (PA), and carotid artery (third tracing from the top, unlabeled) recorded in an open-chest artificially ventilated cat by von Euler and Liljestrand in 1946 (1987) (B). In A, time marks at 1-s intervals are shown in the third tracing from the top; zero pressure baselines are shown at the bottom; and the interval “from a to b (indicates) hydrogen breathing. Asphyxiation by hydrogen produced an increase in pressure in the pulmonary artery and the carotid artery (1530).” In B, changes in inspired gas concentrations are indicated at arrows by numbers [1 = 100% O₂ (from air), 2 = 6.6% CO₂ in O₂, 3 = 100% O₂, 4 = 18.7% CO₂ in O₂, 5 = 100% O₂, 6 = 10.5% O₂ in N₂, 7 = 100% O₂], pressure scales are shown at the right, and time marks at 30-s intervals are shown at the bottom.

FIGURE 3

Representative time courses of pressor responses of isolated lungs or lung lobes to moderate and severe hypoxia (A) and contractile responses of precontracted isolated pulmonary arteries to severe hypoxia (B). In each case, phases of HPV are indicated, as discussed in the text.

FIGURE 4

Possible O₂ sensing pathways. ROS, reactive oxygen species.

FIGURE 5

Pathways of ATP production via glycolysis and mitochondrial oxidative phosphorylation (A) and details of electron transport, proton movement, and production of ATP and reactive O₂ species in mitochondria (B). ANT, adenine nucleotide translocator; I, II, III, and IV indicate mitochondrial electron transport protein complexes; Q, QH₂, and QH^·, ubiquinone, ubiquinol, and ubisemiquinone, respectively. Cytochromes c, c1, b_L. b_H, and aa3 are indicated by their letters. FeS, Rieske Fe-S protein; F₁F₀, F₁F₀ ATP synthetase; SOD, superoxide dismutase; GPX, glutathione peroxidase. Sites of action of commonly used mitochondrial inhibitors (rotenone, myxothiazole, antimycin A, and cyanide) are shown in B.

FIGURE 6

Diagrams of possible mechanisms that explain how hypoxia causes constriction in pulmonary arterial smooth muscle, as proposed by the Redox (A), ROS (B), and energy state/AMP kinase (C) hypotheses. Main and alternative pathways are indicated by black and gray arrows, respectively. K_V, VOCC, SOCC, and NSCC, voltage-dependent K⁺, voltage-operated Ca²⁺, store-operated Ca²⁺, and nonselective cation channels, respectively; E_m, membrane potential; cADPR, cyclic ADP ribose; AMPK, AMP kinase; SR, sarcoplasmic reticulum.

FIGURE 7

Effects of acute hypoxia on intracellular Ca²⁺ concentration ([Ca²⁺]_i) in pulmonary arterial smooth muscle. Pathways that increase [Ca²⁺]_i are shown on the left, while those that decrease [Ca²⁺]_i are on the right. Hypoxia can activate (green) or inhibit (red) these pathways. Whether these effects are probable, possible, or speculative is indicated by solid, dashed, and dotted lines, respectively, as shown in the key at the bottom. With respect to plasma membrane and associated cytosolic signals, TASK-1 is TWIK-related acid-sensitive channel-1; VOCC, K_V, Cl_Ca, SOCC, NSCC, and ROCC indicate voltage-operated Ca²⁺, voltage-dependent K⁺, calcium-dependent Cl⁻, store-operated Ca²⁺, nonselective cation, and receptor-operated Ca²⁺ channels, respectively. NCX, Na-Ca exchanger; A, agonist; R, receptor; PLC, phospholipase C; PIP₂, phosphatidylinositol 4,5-bisphosphate; IP₃, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; PMCA, plasma membrane Ca²⁺-ATPase. With respect to sarcoplasmic reticulum (SR) and associated cytosolic signals, SERCA is sarcoplasmic-endoplasmic reticulum ATPase, IP₃R is IP₃ receptor, RyR is ryanodine receptor, STIM1 is stromal interaction molecule 1, and cADPR is cyclic ADP ribose. With respect to lysosome-like organelles (LLO) and associated cytosolic signals, NAADP is nicotinic acid adenine dinucleotide phosphate, HCX is H-Ca exchanger, and HA is H⁺-ATPase. Mito, mitochondria.

FIGURE 8

Effects of acute hypoxia (4% O₂) on intracellular Ca²⁺ concentration ([Ca²⁺]_i) in rat distal pulmonary arterial smooth muscle cells exposed to normal (Control) or Ca²⁺-free perfusates (2002) (A) and normal perfusate after treatment with nontargeted small interfering RNA (NT siRNA) or siRNA targeted to stromal interaction molecule 1 (STIM1 siRNA) (1138) (B).

FIGURE 9

Effects of acute hypoxia on mitochondrial Ca²⁺. Pathways of Ca²⁺ entry include “rapid mode” uptake (RaM) and a uniporter (U). Ca²⁺ can be stored in the matrix as calcium phosphate complexes or leave the organelle through Ca²⁺ efflux pathways, including mitochondrial H-Ca and Na-Ca exchangers (mHCE, mNCE), the latter driven by the mitochondrial Na-H exchanger (mNHE). Under extreme conditions, the “permeability transition pore (PTP)” may also play a role. Hypoxia may activate (green) or inhibit (red) these pathways. The effects shown are highly speculative (dotted lines) rather than probable (solid lines) or possible (dashed lines) and assume that hypoxia decreased mitochondrial electron transport, proton pumping, and membrane potential. Indeed, as discussed in the text, there is some evidence that the opposite may occur. Components of electron transport, proton pumping, and oxidative phosphorylation are also shown, including the tricarboxlic acid (TCA) cycle, electron transport complexes I-IV, F₁F₀ ATP synthetase (F₁F₀), and adenine nucleotide translocator (ANT). Mitochondrial membrane potential (Δψ_M), generated by transport of H⁺ from the matrix, is shown at its normal value of about −180 mV.

FIGURE 10

Effects of acute hypoxia on determinants of myofilament Ca²⁺ sensitivity in pulmonary arterial smooth muscle. Whether hypoxic activation (green) or inhibition (red) of pathways is probable, possible, or speculative is indicated by solid, dashed, or dotted lines, respectively, as shown in the key at the bottom. CaM, calmodulin; MLCK, myosin light-chain kinase; RhoK, Rho kinase; ILK, integrin-linked kinase; ZIPK, zip kinase; MLC₂₀, 20-kDa regulatory myosin light chain; NOS, NO synthase; GC, guanylate cyclase; PKG, protein kinase G; MLCP, myosin light-chain phosphatase; CPI-17, 17-kDa C-kinase-potentiated phosphatase inhibitor; PKC, protein kinase C; GAP, GTPase-activating proteins; GEF, guanine nucleotide exchange factors; DAG, diacylglycerol. Phosphorylated proteins are indicated by a white “P” in a gold circle.

FIGURE 11

Relation between extracellular [Ca²⁺] and change in isometric force (ΔF) from baseline values measured under Ca²⁺-free conditions in deendothelialized rat distal pulmonary arteries permeabilized with α-toxin and exposed to normoxia (16% O₂) or hypoxia (1% O₂) (2040). Arteries were otherwise untreated (control) or treated with N^ω-nitro-l-arginine methyl ester (l-NAME, 30 μM). ΔF is expressed as a percentage of the contractile response to [KCl] = 80 mM (%KCl₈₀) measured before permeabilization. LSD_.05 is the protected least significant difference at the 0.05 level.

FIGURE 12

Effects of ventilation-perfusion (V̇/Q̇) relationships on oxygen exchange in a 2-compartment lung during normal conditions (A), V̇/Q̇ mismatch without hypoxic pulmonary vasoconstriction (HPV) (B), and V̇/Q̇ mismatch with HPV (C). Values for total ventilation (V̇), inspired O₂ tension (P_IO₂), total cardiac output (Q̇), and mixed venous O₂ concentration (C_mvO₂), tension (P_mvO₂), and hemoglobin saturation (S_mvO₂) shown in A were the same for all conditions. Compartmental ventilation (V̇₁, V̇₂), perfusion (Q̇₁, Q̇₂), ventilation-perfusion ratio (V̇₁/Q̇_1, V̇₂/Q̇₂), the resulting systemic arterial O₂ concentration (C_aO₂, calculated as the perfusion-weighted mean of the O₂ concentrations in blood flowing from each compartment) and corresponding systemic arterial oxyhemoglobin saturation (S_aO₂) and O₂ tension (P_aO₂) are also indicated for each condition. For simplicity, O₂ concentrations were calculated as the product of hemoglobin concentration (15 g/dl), hemoglobin O₂ binding capacity (1.34 vol% per g/dl), and oxyhemoglobin saturation, and ignore the concentration of O₂ physically dissolved in plasma, which would be small at these O₂ tensions. Vol% indicates ml O₂ (STPD)/100 ml blood.

FIGURE 13

Relation between cardiac output and the difference between mean pulmonary arterial and wedge pressures (P_PA-P_W) measured in patients with lung disease. Each point represents the acute effects of inhaled O₂ or another vasodilator (see legend) on mean cardiac output and (P_PA-P_W) expressed as a percent of control values in groups of patients with chronic obstructive lung disease (COPD, left) (7, 14, 96, 182, 381, 480, 804, 836, 907, 940, 948, 1066, 1256, 1303, 1337, 1489, 1791, 1937, 2158) or interstitial lung disease (ILD, right) (15, 236, 531, 607, 687, 907, 1426, 1551). The shaded areas represent all possible loci of points on the control (P_PA-P_W) vs. cardiac output relation, only one of which is known [(P_PA-P_W) = 100; cardiac output = 100]; therefore, movement of the control point to the left of the shaded area indicates pulmonary vasodilation, while movement to the right indicates vasoconstriction.