Pulmonary Endothelium and Pulmonary Hypertension

2009 ◽  
pp. 449-460 ◽  
Author(s):  
Rubin M. Tuder ◽  
Serpil C. Erzurum
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Endothelium

Pathology and Pathobiology of Pulmonary Hypertension

2017 ◽  
Vol 38 (05) ◽  
pp. 571-584 ◽  
Author(s):  
Peter Dorfmüller ◽  
Christophe Guignabert
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Inflammation ◽  
Right Heart Catheterization ◽  
Point Of View ◽  
Heart Catheterization ◽  
Pulmonary Endothelium ◽  
Hemodynamic State ◽  
Pulmonary Arterial ◽  
Genetic And Environmental Factors ◽  
And Migration

Pulmonary hypertension (PH) is a hemodynamic state defined by a mean pulmonary artery pressure ≥ 25 mm Hg during resting right heart catheterization. PH can result from precapillary (arterial) or postcapillary (venous) pathophysiological mechanisms. Interestingly, recent PH pathology has shown that pulmonary arterial or pulmonary venous remodelling are rarely independent phenomena, but frequently occur in combined fashion in lungs from patients suffering from different forms of PH, including pulmonary arterial hypertension (PAH). In PAH, it is now becoming clear that aberrant signals present in vessel wall microenvironment, which is largely orchestrated by dysfunctional pulmonary endothelial cells, are key contributors of the pulmonary vascular remodeling process, fostering proliferation, and survival and migration of resident pulmonary vascular cells such as smooth muscle cells, myofibroblasts, and pericytes. In addition, both genetic and environmental factors are also critical in the development of pulmonary vascular inflammation and chronic impairment of the pulmonary endothelium. This article outlines the current understanding of this disease from the point of view of pathology and pathobiology.

scholarly journals HIF2α–arginase axis is essential for the development of pulmonary hypertension

2016 ◽  
Vol 113 (31) ◽  
pp. 8801-8806 ◽  
Author(s):  
Andrew S. Cowburn ◽  
Alexi Crosby ◽  
David Macias ◽  
Cristina Branco ◽  
Renato D. D. R. Colaço ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Endothelium ◽  
Arginase 1

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

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/ .

scholarly journals S110 Hif2a deletion in the pulmonary endothelium prevents hypoxia-induced pulmonary hypertension

2017 ◽  
Author(s):  
AS Cowburn ◽  
A Crosby ◽  
D Macias-Gutierrez ◽  
M Southwood ◽  
C Branco ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Endothelium

Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature

2008 ◽  
Vol 294 (1) ◽  
pp. L98-L109 ◽  
Author(s):  
David B. Frank ◽  
Jonathan Lowery ◽  
Lynda Anderson ◽  
Monique Brink ◽  
Jeff Reese ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Prolonged Exposure ◽  
Bmp Signaling ◽  
Mutant Mice ◽  
Pulmonary Vasculature ◽  
Cellular Mechanisms ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Endothelium ◽  
Increased Susceptibility

Patients with familial pulmonary arterial hypertension inherit heterozygous mutations of the type 2 bone morphogenetic protein (BMP) receptor BMPR2. To explore the cellular mechanisms of this disease, we evaluated the pulmonary vascular responses to chronic hypoxia in mice carrying heterozygous hypomorphic Bmpr2 mutations ( Bmpr2ΔEx2/+). These mice develop more severe pulmonary hypertension after prolonged exposure to hypoxia without an associated increase in pulmonary vascular remodeling or proliferation compared with wild-type mice. This is associated with defective endothelial-dependent vasodilatation and enhanced vasoconstriction in isolated intrapulmonary artery preparations. In addition, there is a selective decrease in hypoxia-induced, BMP-dependent, endothelial nitric oxide synthase expression and Smad signaling in the intact lungs and in cultured pulmonary microvascular endothelial cells from Bmpr2ΔEx2/+ mutant mice. These findings indicate that the pulmonary endothelium is a target of abnormal BMP signaling in Bmpr2ΔEx2/+ mutant mice and suggest that endothelial dysfunction contributes to their increased susceptibility to hypoxic pulmonary hypertension.

scholarly journals Altered membrane lipid domains limit pulmonary endothelial calcium entry following chronic hypoxia

2011 ◽  
Vol 301 (4) ◽  
pp. H1331-H1340 ◽  
Author(s):  
Michael L. Paffett ◽  
Jay S. Naik ◽  
Melissa A. Riddle ◽  
Steven D. Menicucci ◽  
Antonio J. Gonzales ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Membrane Lipid ◽  
Membrane Cholesterol ◽  
Cholesterol Depletion ◽  
Pulmonary Endothelium ◽  
Caveolin 1 ◽  
Fura 2 ◽  
In Cells

Agonist-induced Ca2+ entry into the pulmonary endothelium depends on activation of both store-operated Ca2+ (SOC) entry and receptor-operated Ca2+ (ROC) entry. We previously reported that pulmonary endothelial cell SOC entry and ROC entry are reduced in chronic hypoxia (CH)-induced pulmonary hypertension. We hypothesized that diminished endothelial Ca2+ entry following CH is due to derangement of caveolin-1 (cav-1) containing cholesterol-enriched membrane domains important in agonist-induced Ca2+ entry. To test this hypothesis, we measured Ca2+ influx by fura-2 fluorescence following application of ATP (20 μM) in freshly isolated endothelial cells pretreated with the caveolar-disrupting agent methyl-β-cyclodextrin (mβCD; 10 mM). Cholesterol depletion with mβCD attenuated agonist-induced Ca2+ entry in control endothelial cells to the level of that from CH rats. Interestingly, endothelial membrane cholesterol was lower in cells isolated from CH rats compared with controls although the density of caveolae did not differ between groups. Cholesterol repletion with a cholesterol:mβCD mixture or the introduction of the cav-1 scaffolding peptide (AP-cav; 10 μM) rescued ATP-induced Ca2+ entry in endothelia from CH arteries. Agonist-induced Ca2+ entry assessed by Mn2+ quenching of fura-2 fluorescence was also significantly elevated by luminal AP-cav in pressurized intrapulmonary arteries from CH rats to levels of controls. Similarly, patch-clamp experiments revealed diminished inward current in response to ATP in cells from CH rats compared with controls that was restored by AP-cav. These data suggest that CH-induced pulmonary hypertension leads to reduced membrane cholesterol that limits the activity of ion channels necessary for agonist-activated Ca2+ entry.

Circulating endothelial cells in pulmonary hypertension

2003 ◽  
Vol 90 (10) ◽  
pp. 698-703 ◽  
Author(s):  
Heiko Golpon ◽  
Robert Hebbel ◽  
Anna Solovey ◽  
Carlyne Cool ◽  
Rubin Tuder ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Peripheral Blood ◽  
Cell Activation ◽  
High Pressures ◽  
Circulating Endothelial Cells ◽  
Pulmonary Vasculature ◽  
Endothelial Cell Activation ◽  
Pulmonary Endothelium ◽  
The Individual

SummaryThe pulmonary endothelium plays a significant role in the pathobiology of Primary Pulmonary Hypertension. A number of diseases, related by a history of vascular injury, are associated with increased numbers of circulating endothelial cells (CECs). We hypothesized that patients with pulmonary hypertension would also have an increased number of circulating endothelial cells due to the high pressures and increased shear stress present within the pulmonary vasculature. We isolated the CECs from 14 patients with pulmonary hypertension, (5 primary and 11 secondary) and compared them to the cells from 12 normal controls. There was a significant increase in the number of CECs in peripheral blood in patients with both PPH and secondary pulmonary hypertension (SPH) when compared to normal volunteers (33.1 +/- 1.9 {PPH} and 27.2 +/- 6.9 {SPH} vs. 3.5 +/- 1.3 {controls}, p < 0.001). The number of circulating endothelial cells in the patient’s peripheral blood correlated significantly with the systolic, diastolic and mean pulmonary artery pressures of the individual. Approximately 50% of the CECs from patients with pulmonary hypertension expressed CD36, a marker of microvascular origin and 25% expressed E-selectin, a marker of endothelial cell activation. Although the origin of the CECs in patients with PH requires further investigation, one possible source is the pulmonary vasculature, and in patients with plexogenic pulmonary hypertension, the plexiform lesions. CECs may provide a non-invasive mean of accessing cells important to the pathobiology of severe pulmonary hypertension.

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