Endothelium-derived relaxing factor activity in rat lung during hypoxic pulmonary vascular remodeling

Zhao, Lan; Crawley, David; Hughes, Judith M.; Evans, Timothy W.; Winter, R. J. D.

doi:10.1152/jappl.1993.74.3.1061

Cited by 33 publications

(26 citation statements)

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“…Pharmacological or genetic inhibition of NO synthase, particularly the endothelial isoform, increases hypoxic pulmonary vasoconstriction in rodents. 17,18 Both inhaling NO 19 and inhibition of cGMP hydrolysis using the phosphodiesterase type 5 inhibitor, sildenafil, 20 reduce acute hypoxia-induced pulmonary hypertension and chronic sildenafil use reduces established pulmonary hypertension in resident highlanders. 21 The most common isoform of sGC is active as a heterodimer, composed of an α1 subunit and a heme-containing β1 subunit, and expressed in the smooth muscle layer of the pulmonary vascular wall.…”

Section: Discussionmentioning

confidence: 99%

α1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders

Wilkins

Aldashev

Wharton

et al. 2014

Circ Cardiovasc Genet

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E nvironmental hypoxia is an important cause of pulmonary hypertension worldwide. Reducing alveolar Po 2 causes pulmonary vasoconstriction.1 Chronic exposure to hypoxia leads to pulmonary vascular remodeling, including increased muscularization of distal arterioles, with extension of muscle into previously unmuscularized vessels, and an increase in the collagen and elastin content of the vessel wall. 2 The increased pressure-load on the right ventricle reduces exercise capacity and can lead to right heart failure. Clinical Perspective on p 929Variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized, both between and within species, and has a genetic basis. The Tibetans are notably well-adapted to high-altitude life, having lived >3000 m for thousands of years, 3 and are less susceptible than recent migrants to high-altitude pulmonary hypertension. 4 The Kyrgyz have inhabited the high plains of the Tien-Shen and Background-Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. Highaltitude residents who do not develop pulmonary hypertension may host protective gene mutations. Methods and Results-Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an α 1 -A680T soluble guanylate cyclase (sGC) variant. Expression of the α 1 -A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified α 1 -A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. Conclusions-The α 1 -A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude. We hypothesized that adult Kyrgyz highlanders who do not experience pulmonary hypertension at altitude may host gene mutations that are protective. We compared the exomes of resident ethnic Kyrgyz highlanders with and without pulmonary hypertension to identify candidate genes that may influence the pulmonary vascular response to hypoxia. An activating mutation was identified in the GUCY1A3 gene, encoding the α subunit of soluble guanylate cyclase (sGC). Methods SubjectsIn successive ...

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Section: Discussionmentioning

confidence: 99%

α1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders

Wilkins

Aldashev

Wharton

et al. 2014

Circ Cardiovasc Genet

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“…48 -54 Whereas several investigators have found a reduced HPV response after long-term exposure to hypoxia, 48 -54 other groups have reported an enhanced response or no change in HPV after exposure to a low O 2 tension. 48,49 In addition to these 2 factors (animal species and length of hypoxic exposure), we showed that the effect of chronic hypoxia on acute hypoxia-induced responses depended on the localization of the PASMCs within the media. These results emphasize regional differences in PASMC populations within the media.…”

Section: Effects Of Chronic Hypoxia On Pasmc Morphology and Responsesmentioning

confidence: 88%

RhoA Activation by Hypoxia in Pulmonary Arterial Smooth Muscle Cells Is Age and Site Specific

Bailly

Ridley

Hall

et al. 2004

Circulation Research

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Abstract-Hypoxia induces vasoconstriction of pulmonary arteries through contraction of smooth muscle cells (SMCs).The GTPase RhoA regulates smooth muscle contractility and actin cytoskeletal remodeling through the Rho-associated kinase (ROCK). We previously found that the postnatal fall in pulmonary vascular resistance was associated with actin cytoskeletal remodeling in porcine pulmonary arterial SMCs (PASMCs) in vivo. Here, we investigated the effects of acute and chronic hypoxia on the morphology and RhoA activity of PASMCs from fetal and neonatal piglets. Acute hypoxia enhanced actin stress fiber formation and RhoA activity in both inner and outer medial PASMCs from the fetus but only in the inner medial PASMCs from normal 3-day-old piglets. The increased stress fiber formation was dependent on Rho and ROCK. In outer medial PASMCs from 14-day-old animals, acute hypoxia decreased RhoA activity. Interestingly, outer medial PASMCs from animals exposed to chronic hypoxia had fewer stress fibers associated with a lower basal RhoA activity. Treatment of PASMCs from normal 3-day-old piglets with Rho or ROCK inhibitors for 24 hours induced a similar morphology. Rac activity was not altered by either acute or chronic hypoxia. These data show that acute hypoxia induces RhoA activation only in PASMCs from young animals, whereas chronic hypoxia selectively downregulates RhoA activity in outer medial PASMCs leading to an altered phenotype. Key Words: pulmonary Ⅲ smooth muscle cell Ⅲ hypoxia Ⅲ Rho Ⅲ Rac P ulmonary vascular resistance is high in utero and normally falls at birth when pulmonary arteries dilate and blood flow increases. Postnatal dilatation is characterized by elongation and thinning of medial pulmonary arterial smooth muscle cells (PASMCs) with associated actin cytoskeletal remodeling, transient disassembly of the actin cytoskeleton, and a reduction in total actin content. 1,2 Cytoskeletal change is most marked in inner medial SMCs. Failure to adapt normally to extrauterine life causes persistent pulmonary hypertension of the newborn (PPHN). The pulmonary arteries remain undilated and thick walled. 3,4 Hypoxia is a common cause of PPHN in human infants, and newborn piglets exposed to chronic hypoxia develop pulmonary hypertension and show pulmonary vascular abnormalities similar to those seen in sick infants. 5,6 Actin cytoskeleton remodeling is impaired in the PASMCs of chronically hypoxic newborn piglets, although the normal postnatal increase in proportion of monomer actin does take place. 2 These observations suggest that chronic hypoxia causes disregulation of actin filament turnover in the newborn.Rho-family GTPases are involved in actin remodeling: Rho regulates the formation of stress fibers and focal adhesions, 7,8 whereas Rac induces lamellipodia and membrane ruffles. 9 -11 Rho cycles between a GDP-bound inactive state and a GTP-bound active state, and when bound to GTP, activates its downstream targets, including the serine/threonine kinase Rho-associated kinase (ROCK). 12 The Rho-ROCK pathway c...

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“…Moreover, while some groups have evidence for impaired nitric oxide pro-30 mmHg) was two-fold greater in the WKY lung compared with the F344 lung (Figure 2), with no duction in the lungs of rats [26 ] kept in a chronic hypoxic environment, we and others have found that overlap in the response between the two strains. Chronic exposure of both rat strains to 10%O 2 in a normobaric synthesis is preserved or possible increased [23,24].…”

Section: Abstract Hypoxia Vasoactive Factors Genetics Rat Strainsmentioning

confidence: 94%

“…In the of this amino acid have been used by several groups to explore the role of nitric oxide in HPV [22][23][24]. There search for humoral mediators many vasoactive substances have been considered as candidates.…”

Section: Abstract Hypoxia Vasoactive Factors Genetics Rat Strainsmentioning

confidence: 99%

The regulation of pulmonary vascular tone

Wilkins

Zhao

Al-Tubuly

1996

Brit J Clinical Pharma

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1 The ability to manipulate pharmacologically pulmonary vascular tone independent of effects on systemic blood vessels is a desirable objective. Elucidation of the biochemical mechanisms underlying hypoxia-induced pulmonary vasoconstriction ( HPV) may permit preferential targeting of the pulmonary circulation. 2 Here we review our studies of the role of locally synthesized candidate vasoactive factors in HPV. In addition, we present data demonstrating an attenuated pressor response to hypoxia in the pulmonary circulation of Fischer 344 rats compared with the Wistar-Kyoto ( WKY) rat strain. 3 We propose that a systematic genome-wide search using the HPV phenotype and a panel of highly informative microsatellite markers will elucidate the genetic loci underlying the difference in susceptibility to HPV in these two rat strains and provide a valuable and novel insight into the factors that determine the HPV response. Keywords hypoxia vasoactive factors genetics rat strainsThe clinical problem optimal. There are obvious practical difficulties with the chronic infusion of compounds and there are concerns about the toxicity of chronic nitric oxide administration. The normal adult pulmonary circulation is a lowpressure, low-resistance system with little or no resting Clearly, the treatment of pulmonary hypertension would benefit from a more comprehensive range of drugs that vascular tone. Pulmonary artery pressure may be increased, however, in a number of clinical situations, target selectively the pulmonary circulation. such as in patients with chronic hypoxic lung disease or a left-to-right intracardiac shunt, and, less frequently, as a primary event. In the long-term, pulmonary hypertension leads to right ventricular hypertrophy, heart failure Hypoxia-induced pulmonary vasoconstriction (HPV ) and premature death.The current treatment of pulmonary hypertension is Oxygen tension is a major regulator of pulmonary vascular tone. Ventilation of lungs with an hypoxic unsatisfactory [1,2]. Oxygen is an effective pulmonary vasodilator in pulmonary hypertension secondary to gaseous mixture (i.e. decreasing PO 2 from~130 to 30-40 mmHg) leads to acute pulmonary vasoconstricchronic obstructive lung disease [3 ] and has been reported to be beneficial in other forms of pulmonary tion, most pronounced in precapillary arterioles [9 ]. Constriction is also observed in isolated pulmonary hypertension [4, 5 ], but it is inconvenient to administer, relatively expensive and has to be given for at least 12 h arteries (the degree of vasoconstriction correlating inversely with diminishing vessel size) [10][11][12] and per day. A number of more conventional vasodilators have been examined, but the doses required to reduce isolated pulmonary vascular smooth muscle cells [11 ] perfused at low oxygen tension (~40 mmHg). the elevated pulmonary artery pressure are usually so high that they are associated with symptomaticIn contrast, systemic vessels in the intact rat [13 ], mesenteric resistance vessels perfused in situ [ 14] and and unacceptab...

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Endothelium-derived relaxing factor activity in rat lung during hypoxic pulmonary vascular remodeling

Cited by 33 publications

References 0 publications

α1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders

α1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders

RhoA Activation by Hypoxia in Pulmonary Arterial Smooth Muscle Cells Is Age and Site Specific

The regulation of pulmonary vascular tone

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