The Problem of Medial Hypertrophy in Pulmonary Hypertension

Respiration ◽  
1962 ◽  
Vol 19 (5) ◽  
pp. 411-417 ◽  
Author(s):  
David S. Short
Keyword(s):  
Pulmonary Hypertension ◽  
Medial Hypertrophy

scholarly journals Purinergic dysregulation in pulmonary hypertension

2016 ◽  
Vol 311 (1) ◽  
pp. H286-H298 ◽  
Author(s):  
Scott H. Visovatti ◽  
Matthew C. Hyman ◽  
Sascha N. Goonewardena ◽  
Anuli C. Anyanwu ◽  
Yogendra Kanthi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Potential Role ◽  
Purinergic Signaling ◽  
Continuous Administration ◽  
P2x1 Receptor ◽  
Pulmonary Endothelium ◽  
Pulmonary Arterial ◽  
Medial Hypertrophy

Despite the fact that nucleotides and adenosine help regulate vascular tone through purinergic signaling pathways, little is known regarding their contributions to the pathobiology of pulmonary arterial hypertension, a condition characterized by elevated pulmonary vascular resistance and remodeling. Even less is known about the potential role that alterations in CD39 (ENTPD1), the ectonucleotidase responsible for the conversion of the nucleotides ATP and ADP to AMP, may play in pulmonary arterial hypertension. In this study we identified decreased CD39 expression on the pulmonary endothelium of patients with idiopathic pulmonary arterial hypertension. We next determined the effects of CD39 gene deletion in mice exposed to normoxia or normobaric hypoxia (10% oxygen). Compared with controls, hypoxic CD39−/− mice were found to have a markedly elevated ATP-to-adenosine ratio, higher pulmonary arterial pressures, more right ventricular hypertrophy, more arterial medial hypertrophy, and a pro-thrombotic phenotype. In addition, hypoxic CD39−/− mice exhibited a marked increase in lung P2X1 receptors. Systemic reconstitution of ATPase and ADPase enzymatic activities through continuous administration of apyrase decreased pulmonary arterial pressures in hypoxic CD39−/− mice to levels found in hypoxic CD39+/+ controls. Treatment with NF279, a potent and selective P2X1 receptor antagonist, lowered pulmonary arterial pressures even further. Our study is the first to implicate decreased CD39 and resultant alterations in circulating purinergic signaling ligands and cognate receptors in the pathobiology of pulmonary arterial hypertension. Reconstitution and receptor blocking experiments suggest that phosphohydrolysis of purinergic nucleotide tri- and diphosphates, or blocking of the P2X1 receptor could serve as treatment for pulmonary arterial hypertension. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/purinergic-dysregulation-in-pulmonary-hypertension/ .

Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation

2000 ◽  
Vol 279 (5) ◽  
pp. C1540-C1549 ◽  
Author(s):  
Oleksandr Platoshyn ◽  
Vera A. Golovina ◽  
Colleen L. Bailey ◽  
Alisa Limsuwan ◽  
Stefanie Krick ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Cell Growth ◽  
Pulmonary Artery ◽  
Critical Role ◽  
Membrane Depolarization ◽  
Kv Channels ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Artery Smooth Muscle ◽  
Medial Hypertrophy

Pulmonary vasoconstriction and vascular medial hypertrophy greatly contribute to the elevated pulmonary vascular resistance in patients with pulmonary hypertension. A rise in cytosolic free Ca2+ ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) triggers vasoconstriction and stimulates cell growth. Membrane potential ( E m) regulates [Ca2+]cyt by governing Ca2+influx through voltage-dependent Ca2+ channels. Thus intracellular Ca2+ may serve as a shared signal transduction element that leads to pulmonary vasoconstriction and vascular remodeling. In PASMC, activity of voltage-gated K+(Kv) channels regulates resting E m. In this study, we investigated whether changes of Kv currents [ I K(V)], E m, and [Ca2+]cyt affect cell growth by comparing these parameters in proliferating and growth-arrested PASMC. Serum deprivation induced growth arrest of PASMC, whereas chelation of extracellular Ca2+ abolished PASMC growth. Resting [Ca2+]cyt was significantly higher, and resting E m was more depolarized, in proliferating PASMC than in growth-arrested cells. Consistently, whole cell I K(V) was significantly attenuated in PASMC during proliferation. Furthermore, E mdepolarization significantly increased resting [Ca2+]cyt and augmented agonist-mediated rises in [Ca2+]cyt in the absence of extracellular Ca2+. These results demonstrate that reduced I K(V), depolarized E m, and elevated [Ca2+]cyt may play a critical role in stimulating PASMC proliferation. Pulmonary vascular medial hypertrophy in patients with pulmonary hypertension may be partly caused by a membrane depolarization-mediated increase in [Ca2+]cyt in PASMC.

THE REVERSIBILITY OF PULMONARY HYPERTENSION IN PATIENTS WITH CYSTIC FIBROSIS

PEDIATRICS ◽  
1967 ◽  
Vol 39 (1) ◽  
pp. 24-35
Author(s):  
Leslie L. Kelminson ◽  
Ernest K. Cotton ◽  
John H. K. Vogel
Keyword(s):  
Cystic Fibrosis ◽  
Pulmonary Hypertension ◽  
Control Level ◽  
Repeated Administration ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Pulmonary Vessel ◽  
Sustained Reduction ◽  
Medial Hypertrophy ◽  
Arterial Po2

1. The present study was concerned with the evaluation of the acute and chronic effects of tolazoline, O2, and sleep on the pulmonary circulation of six subjects with cystic fibrosis and pulmonary hypertension. 2. Right heart catheterization was performed and observations were made at rest, after tolazoline and after O2. In four subjects, changes in pulmonary artery pressure (PAP) induced by various agents and sleep were observed for periods ranging from 3 hours to 4 days. 3. Resting mean PAP ranged from 22 to 67 mm Hg; arterial PO2 from 37 to 47 mm Hg; pH from 7.252 to 7.408, cardiac index from 2.64 to 3.91 1/min/m2, and total pulmonary resistance (TPR) from 440 to 1,330 dynes sec cm-5-m2. 4. Following tolazoline, the average mean PAP dropped from 51 to 28 mm Hg, average cardiac output rose from 3.20 to 4.08 1/min/m2; TPR dropped from 880 to normal. This decrease in PAP and TPR was achieved with little change in either pH or arterial pO2. 5. The addition of O2 to tolazoline lowered the mean PAP further by 8 mm Hg. 6. Observations were made during sleep in three of the patients. In each, there was an increase in PAP ranging from 9 to 23 mm Hg. 7. Repeated administration of tolazoline resulted both in progressively lower PAP and less tendency for its return to control level. 8. Postmortem pulmonary arteriograms and histological examination of the pulmonary vessels were performed in one patient. Despite the presence of numerous abscesses and diffuse bronchopneumonia, the pulmonary vessel was found to be relatively normal. Only medial hypertrophy of the small arterioles was seen. 9. The factors involved in the development of hypoxic pulmonary hypertension and possible mechanisms by which tolazoline effects acute and sustained reduction of PAP are discussed. 10. It is concluded that acute and repetitive pharmacologic treatment is effective in the reduction of pulmonary hypertension in patients with cystic fibrosis. Further, it is suggested that patients with cystic fibrosis and reactive pulmonary hypertension would benefit from residing at sea level.

scholarly journals Role of epigenetics in pulmonary hypertension

2014 ◽  
Vol 306 (12) ◽  
pp. C1101-C1105 ◽  
Author(s):  
Tara V. Saco ◽  
Prasanna Tamarapu Parthasarathy ◽  
Young Cho ◽  
Richard F. Lockey ◽  
Narasaiah Kolliputi
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Histone Deacetylase Inhibitors ◽  
Dna Methyltransferases ◽  
Lesion Formation ◽  
Plexiform Lesion ◽  
Medial Hypertrophy ◽  
Pathologic Processes ◽  
Epigenetic Research

A significant amount of research has been conducted to examine the pathologic processes and epigenetic mechanisms contributing to peripheral hypertension. However, few studies have been carried out to understand the vascular remodeling behind pulmonary hypertension (PH), including peripheral artery muscularization, medial hypertrophy and neointima formation in proximal arteries, and plexiform lesion formation. Similarly, research examining some of the epigenetic principles that may contribute to this vascular remodeling, such as DNA methylation and histone modification, is minimal. The understanding of these principles may be the key to developing new and more effective treatments for PH. The purpose of this review is to summarize epigenetic research conducted in the field of hypertension that could possibly be used to understand the epigenetics of PH. Possible future therapies that could be pursued using information from these studies include selective histone deacetylase inhibitors and targeted DNA methyltransferases. Both of these could potentially be used to silence proproliferative or antiapoptotic genes that lead to decreased smooth muscle cell proliferation. Epigenetics may provide a glimmer of hope for the eventual improved treatment of this highly morbid and debilitating disease.

The endothelin system in pulmonary hypertension

2003 ◽  
Vol 81 (6) ◽  
pp. 542-554 ◽  
Author(s):  
René P Michel ◽  
David Langleben ◽  
Jocelyn Dupuis
Keyword(s):  
Clinical Trials ◽  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Tissue Expression ◽  
Vascular Endothelial ◽  
Receptor Antagonists ◽  
New Class ◽  
Endothelin System ◽  
Pulmonary Arterial ◽  
Medial Hypertrophy

Pulmonary hypertension (PH) may result from numerous clinical entities affecting the pulmonary circulation primarily or secondarily. It is recognized that vascular endothelial dysfunction contributes to the development and perpetuation of PH by creating an imbalance between vasodilating and antiproliferative forces and between vasoconstric tive and proliferative forces. In that context, endothelin-1 (ET-1) overproduction was rapidly targeted as a plausible contributor to the pathogenesis of PH. The lung is recognized as the major site for ET production and clearance. In all animal models of PH studied, circulating plasma ET-1 levels are elevated, accompanied by an increase in lung tissue expression of the peptide. The use of selective ETA and dual ETA–ETB receptor antagonists in these models both in prevention and in therapeutic studies have confirmed the contribution of ET-1 to the rise in pulmonary vascular tone, pulmonary medial hypertrophy, and right ventricular hypertrophy. This is found consistently in models affecting the pulmonary circulation primarily or producing PH secondarily. Recent clinical trials in patients with pulmonary arterial hypertension have confirmed the therapeutic effectiveness of ET-receptor antagonists in humans. We offer a systematic review of the pathogenic role of the ET system in the development of PH as well as the rationale behind the preclinical and ongoing clinical trials with this new class of agents.Key words: pulmonary circulation, pulmonary pathology, receptor, preclinical studies, clinical studies, antagonist.

Pulmonary Hypertension Caused by Medial Hypertrophy Associated With Aortic Stenosis and Preductal Coarctation

1997 ◽  
Vol 64 (1) ◽  
pp. 244-247 ◽  
Author(s):  
Masaki Aota ◽  
Shin-ichi Nomoto ◽  
Shigeo Yamaki ◽  
Toshihiko Ban
Keyword(s):  
Pulmonary Hypertension ◽  
Aortic Stenosis ◽  
Medial Hypertrophy

Pulmonary Hypertensive Changes Secondary to COVID-19 Pneumonia in a Chronically SARS-CoV-2-Infected Bilateral Lung Explant

2021 ◽  
pp. 106689692110642
Author(s):  
Joseph M. Rohr ◽  
Heather Strah ◽  
David Berkheim ◽  
Aleem Siddique ◽  
Stanley J. Radio ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Complex Disease ◽  
The Novel ◽  
Long Term Effects ◽  
Hypoxic Respiratory Failure ◽  
Bilateral Lung ◽  
Medial Hypertrophy ◽  
Novel Coronavirus ◽  
Chronic Course

COVID-19, the syndrome caused by the novel coronavirus SARS-CoV-2, has spread throughout the world, causing the death of at least three million people. For the over 81 million who have recovered, however, the long-term effects are only beginning to manifest. We performed a bilateral lung transplant on a 31-year-old male patient for chronic hypoxic respiratory failure, severe pulmonary hypertension and radiographically identified pulmonary fibrosis five months after an acute COVID-19 infection. The explant demonstrated moderate pulmonary vascular remodeling with intimal thickening and medial hypertrophy throughout, consistent with pulmonary hypertension. The parenchyma demonstrated an organizing lung injury in the proliferative phase, with severe fibrosis, histiocytic proliferation, type II pneumocyte hyperplasia, and alveolar loss consistent with known COVID-19 pneumonia complications. This report highlights a novel histologic finding in severe, chronic COVID-19. Although the findings in acute COVID-19 pneumonia have been well-examined at autopsy, the chronic course of this complex disease is not yet understood. The case presented herein suggests that COVID-induced pulmonary hypertension may become more common as more patients survive severe SARS-CoV-2-related pneumonia. Pulmonologists and pulmonary pathologists should be aware of this possible association and look for the clinical, radiographic, and histologic criteria in the appropriate clinical setting.

scholarly journals Critical Role of Caveolin-1 Loss/Dysfunction in Pulmonary Hypertension

2021 ◽  
Vol 9 (4) ◽  
pp. 58
Author(s):  
Rajamma Mathew
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Membrane Protein ◽  
Critical Role ◽  
High Morbidity ◽  
Caveolin 1 ◽  
Enhanced Expression ◽  
Medial Hypertrophy

Pulmonary hypertension (PH) is a rare disease with a high morbidity and mortality rate. A number of systemic diseases and genetic mutations are known to lead to PH. The main features of PH are altered vascular relaxation responses and the activation of proliferative and anti-apoptotic pathways, resulting in pulmonary vascular remodeling, elevated pulmonary artery pressure, and right ventricular hypertrophy, ultimately leading to right heart failure and premature death. Important advances have been made in the field of pulmonary pathobiology, and several deregulated signaling pathways have been shown to be associated with PH. Clinical and experimental studies suggest that, irrespective of the underlying disease, endothelial cell disruption and/or dysfunction play a key role in the pathogenesis of PH. Endothelial caveolin-1, a cell membrane protein, interacts with and regulates several transcription factors and maintains homeostasis. Disruption of endothelial cells leads to the loss or dysfunction of endothelial caveolin-1, resulting in reciprocal activation of proliferative and inflammatory pathways, leading to cell proliferation, medial hypertrophy, and PH, which initiates PH and facilitates its progression. The disruption of endothelial cells, accompanied by the loss of endothelial caveolin-1, is accompanied by enhanced expression of caveolin-1 in smooth muscle cells (SMCs) that leads to pro-proliferative and pro-migratory responses, subsequently leading to neointima formation. The neointimal cells have low caveolin-1 and normal eNOS expression that may be responsible for promoting nitrosative and oxidative stress, furthering cell proliferation and metabolic alterations. These changes have been observed in human PH lungs and in experimental models of PH. In hypoxia-induced PH, there is no endothelial disruption, loss of endothelial caveolin-1, or enhanced expression of caveolin-1 in SMCs. Hypoxia induces alterations in membrane composition without caveolin-1 or any other membrane protein loss. However, caveolin-1 is dysfunctional, resulting in cell proliferation, medial hypertrophy, and PH. These alterations are reversible upon removal of hypoxia, provided there is no associated EC disruption. This review examined the role of caveolin-1 disruption and dysfunction in PH.

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