Pulmonary Artery Smooth Muscle Contraction Research Articles

Comparative Transcriptome Analysis of Gayal (Bos frontalis), Yak (Bos grunniens), and Cattle (Bos taurus) Reveal the High-Altitude Adaptation.

Gayal and yak are well adapted to their local high-altitude environments, yet the transcriptional regulation difference of the plateau environment among them remains obscure. Herein, cross-tissue and cross-species comparative transcriptome analyses were performed for the six hypoxia-sensitive tissues from gayal, yak, and cattle. Gene expression profiles for all single-copy orthologous genes showed tissue-specific expression patterns. By differential expression analysis, we identified 3,020 and 1,995 differentially expressed genes (DEGs) in at least one tissue of gayal vs. cattle and yak vs. cattle, respectively. Notably, we found that the adaptability of the gayal to the alpine canyon environment is highly similar to the yak living in the Qinghai-Tibet Plateau, such as promoting red blood cell development, angiogenesis, reducing blood coagulation, immune system activation, and energy metabolism shifts from fatty acid β-oxidation to glycolysis. By further analyzing the common and unique DEGs in the six tissues, we also found that numerous expressed regulatory genes related to these functions are unique in the gayal and yak, which may play important roles in adapting to the corresponding high-altitude environment. Combined with WGCNA analysis, we found that UQCRC1 and COX5A are the shared differentially expressed hub genes related to the energy supply of myocardial contraction in the heart-related modules of gayal and yak, and CAPS is a shared differential hub gene among the hub genes of the lung-related module, which is related to pulmonary artery smooth muscle contraction. Additionally, EDN3 is the unique differentially expressed hub gene related to the tracheal epithelium and pulmonary vasoconstriction in the lung of gayal. CHRM2 is a unique differentially expressed hub gene that was identified in the heart of yak, which has an important role in the autonomous regulation of the heart. These results provide a basis for further understanding the complex transcriptome expression pattern and the regulatory mechanism of high-altitude domestication of gayal and yak.

Potentiating TMEM16A does not stimulate airway mucus secretion or bronchial and pulmonary arterial smooth muscle contraction.

The calcium‐activated chloride channel (CaCC) TMEM16A enables chloride secretion across several transporting epithelia, including in the airways. Additional roles for TMEM16A have been proposed, which include regulating mucus production and secretion and stimulating smooth muscle contraction. The aim of the present study was to test whether the pharmacological regulation of TMEM16A channel function, could affect any of these proposed biological roles in the airways. In vitro, neither a potent and selective TMEM16A potentiator (ETX001) nor the potent TMEM16A inhibitor (Ani9) influenced either baseline mucin release or goblet cell numbers in well‐differentiated primary human bronchial epithelial (HBE) cells. In vivo, a TMEM16A potentiator was without effect on goblet cell emptying in an IL‐13 stimulated goblet cell metaplasia model. Using freshly isolated human bronchi and pulmonary arteries, neither ETX001 or Ani9 had any effect on the contractile or relaxant responses of the tissues. In vivo, ETX001 also failed to influence either lung or cardiovascular function when delivered directly into the airways of telemetered rats. Together, these studies do not support a role for TMEM16A in the regulation of goblet cell numbers or baseline mucin release, or on the regulation of airway or pulmonary artery smooth muscle contraction.

Chloride channels and α 1-adrenoceptor-mediated pulmonary artery smooth muscle contraction: effect of pulmonary hypertension

Noradrenaline induced concentration-dependent contractions of pulmonary artery segments from control and monocrotaline-treated rats. There was a significant decrease in the maximum response but not sensitivity in artery segments from monocrotaline-treated rats. At a concentration (10 −6 M) that abolished KCl-induced contraction, nifedipine attenuated but did not abolish, noradrenaline-induced contraction in both groups. However, noradrenaline-induced contraction in artery segments from pulmonary hypertensive rats was more susceptible to inhibition by nifedipine. Bumetanide (10 −4 M), a chloride transport inhibitor and niflumic acid, a chloride channel inhibitor, reduced noradrenaline-induced contraction of the pulmonary artery in control and pulmonary hypertensive groups. These compounds were more effective in ring segments from pulmonary hypertensive rats. It was concluded that activation of chloride channels was involved in noradrenaline-induced contraction and that the contribution of chloride channels was enhanced in pulmonary hypertensive rats.

Role of PKC, tyrosine kinases, and Rho kinase in alpha-adrenoreceptor-mediated PASM contraction.

Our objectives were to identify the relative contributions of intracellular free Ca2+ concentration ([Ca2+]i) and myofilament Ca2+ sensitivity in the pulmonary artery smooth muscle (PASM) contractile response to the alpha-adrenoreceptor agonist phenylephrine (PE) and to assess the role of PKC, tyrosine kinases (TK), and Rho kinase (ROK) in that response. Our hypothesis was that multiple signaling pathways are involved in the regulation of [Ca2+]i, myofilament Ca2+ sensitization, and vasomotor tone in response to alpha-adrenoreceptor stimulation of PASM. Simultaneous measurement of [Ca2+]i and isometric tension was performed in isolated canine pulmonary arterial strips loaded with fura 2-AM. PE-induced tension development was due to sarcolemmal Ca2+ influx, Ca2+ release from inositol 1,4,5-trisphosphate-dependent sarcoplasmic reticulum Ca2+ stores, and myofilament Ca2+ sensitization. Inhibition of either PKC or TK partially attenuated the sarcolemmal Ca2+ influx component and the myofilament Ca2+ sensitizing effect of PE. Combined inhibition of PKC and TK did not have an additive attenuating effect on PE-induced Ca2+ sensitization. ROK inhibition slightly decreased [Ca2+]i but completely inhibited myofilament Ca2+ sensitization. These results indicate that PKC and TK activation positively regulate sarcolemmal Ca2+ influx in response to alpha-adrenoreceptor stimulation in PASM but have relatively minor effects on myofilament Ca2+ sensitivity. ROK is the predominant pathway mediating PE-induced myofilament Ca2+ sensitization.

A Redox Role for Cyclic ADP-Ribose

Hypoxic pulmonary vasoconstriction is a normal physiological response that coordinates pulmonary perfusion to respiratory ventilation. NADH (reduced nicotinamide adenine dinucleotide) is thought to have a role in pulmonary artery contraction. Oxidized NAD (NAD+) is a substrate used by ADP-ribosyl cyclase to make cyclic ADP-ribose (cADPR), which regulates ryanodine receptor-mediated Ca2+ release. Wilson et al. investigated whether the ratio of NAD+:NADH in pulmonary arteries functioned as an oxido-reductive sensing rheostat to control pulmonary vasoconstriction. cADPR production in pulmonary artery smooth muscle homogenates was increased when NADH was added, but concentrations of NAD+ were constant. This result suggests that the enzymatic breakdown of cADPR by cADPR hydrolase is inhibited by the presence of NADH. Pulmonary artery sections incubated in hypoxic conditions produced greatly increased amounts of cADPR, whereas, in other experiments, vasoconstriction was inhibited by pretreatment with a cADPR antagonist, indicating that cADPR, produced in response to lower oxygen tension, can mediate pulmonary artery smooth muscle contraction. The authors suggest that cADPR, cADP hydrolase, and ADP-ribosylase function together to link the redox state of pulmonary smooth cells to Ca2+ release from the ryanodine receptor-regulated sarcoplasmic reticulum and consequent vasoconstriction.H. L. Wilson, M. Dipp, J. M. Thomas, C. Lad, A. Galione, A. M. Evans, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor: A primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction. J. Biol. Chem. 276, 11180-11188 (2001). [Abstract] [Full Text]

A Redox Role for Cyclic ADP-Ribose

Hypoxic pulmonary vasoconstriction is a normal physiological response that coordinates pulmonary perfusion to respiratory ventilation. NADH (reduced nicotinamide adenine dinucleotide) is thought to have a role in pulmonary artery contraction. Oxidized NAD (NAD + ) is a substrate used by ADP-ribosyl cyclase to make cyclic ADP-ribose (cADPR), which regulates ryanodine receptor-mediated Ca 2+ release. Wilson et al. investigated whether the ratio of NAD + :NADH in pulmonary arteries functioned as an oxido-reductive sensing rheostat to control pulmonary vasoconstriction. cADPR production in pulmonary artery smooth muscle homogenates was increased when NADH was added, but concentrations of NAD + were constant. This result suggests that the enzymatic breakdown of cADPR by cADPR hydrolase is inhibited by the presence of NADH. Pulmonary artery sections incubated in hypoxic conditions produced greatly increased amounts of cADPR, whereas, in other experiments, vasoconstriction was inhibited by pretreatment with a cADPR antagonist, indicating that cADPR, produced in response to lower oxygen tension, can mediate pulmonary artery smooth muscle contraction. The authors suggest that cADPR, cADP hydrolase, and ADP-ribosylase function together to link the redox state of pulmonary smooth cells to Ca 2+ release from the ryanodine receptor-regulated sarcoplasmic reticulum and consequent vasoconstriction. H. L. Wilson, M. Dipp, J. M. Thomas, C. Lad, A. Galione, A. M. Evans, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor: A primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction. J. Biol. Chem. 276 , 11180-11188 (2001). [Abstract] [Full Text]