Persistence of the fetal pattern of tropoelastin gene expression in severe neonatal bovine pulmonary hypertension.

Stenmark, Kurt R.; Durmowicz, Anthony G.; Roby, Jill D.; Mecham, Robert P.; Parks, William C.

doi:10.1172/jci117077

Cited by 41 publications

(17 citation statements)

References 37 publications

(36 reference statements)

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“…Note, phenotypic changes in SMCs, from a contractile to a proliferative phenotype, were not measured, nor were other potentially important vascular wall elements such as fibronectin, proteoglycans, and degree of protein cross-linking. The increases in collagen and elastin thickness were most likely due to the upregulation of procollagen and tropoelastin genes in response to hypoxia-induced pulmonary hypertension as previously described for calves (8,38).…”

Section: Discussionsupporting

confidence: 56%

“…In response to hypoxia, the most dramatic structural vascular changes in rats are in the main (hilar) pulmonary arteries, which thicken through protein accumulation, and in the small arteries and arterioles, which thicken medially through muscularization (30). Various growth-related genes have been shown to modulate these structural changes in hypoxia-induced pulmonary hypertension, including transforming growth factor-␤ (34), platelet-derived growth factor (22), endothelin-1, and endothelin receptor (7,9,25,33), as well as extracellular matrix-related genes such as the type I procollagen, tropoelastin, and fibronectin genes (8,38). However, the mechanical changes resulting from these structural and gene-level changes are not well understood.…”

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confidence: 99%

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Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension

Kobs

Muvarak

Eickhoff

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

133

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Right heart failure due to pulmonary hypertension causes significant morbidity and mortality. To study the linked vascular mechanical and biological changes that are induced by pulmonary hypertension, we mechanically tested isolated left main pulmonary arteries from mice exposed to chronic hypobaric hypoxia and performed histological assays on contralateral vessels. In isolated vessel tests, hypoxic vessels stretched less in response to pressure than controls at all pressure levels. Given the short length and large diameter of the pulmonary artery, the tangent Young's modulus could not be measured; instead, an effective elastic modulus was calculated that increased significantly with hypoxia [(280 kPa (SD 53) and 296 kPa (SD 50) for 10 and 15 days, respectively, vs. 222 kPa (SD 35) for control; P < 0.02)]. Hypoxic vessels also had higher damping coefficients [(0.063 (SD 0.017) and 0.054 (SD 0.014) for 10 and 15 days, respectively, vs. 0.033 (SD 0.016) for control; P < 0.002)], indicating increased energy dissipation. The increased stiffness with hypoxia correlated with an increase in collagen thickness (percent collagen multiplied by wall thickness) as well as the sum of elastin and collagen thicknesses measured histologically in the artery wall. These results highlight the mechanobiological changes in the pulmonary vasculature that occur in response to hypoxia-induced pulmonary hypertension. Furthermore, they demonstrate significant vascular mechanical and biological changes that would increase pulmonary vascular impedance, leading to right heart failure.

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Section: Discussionsupporting

confidence: 56%

mentioning

confidence: 99%

Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension

Kobs

Muvarak

Eickhoff

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

133

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“…(ii) Evaluation of plexiform lesions in primary pulmonary hypertension revealed intense perivascular inflammatory activity accompanied by the expression of extracellular matrix proteins that were associated with increased growth and differentiation of abnormal endothelial cells (15). (iii) Pulmonary hypertension due to hypoxia led to an increased expression of nonphysiological extracellular matrix proteins (16). (iv) In rats, pulmonary artery pressure rose significantly due to bacterial infection of the lung caused by pseudomonas aeruginosa (17).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue.

Ziesche

Petkov

Williams

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor a on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 113, or tumor necrosis factor a augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.The pathogenesis of pulmonary hypertension is unknown. However, both experimental and clinical evidence indicate that hypoxia or inflammation dramatically aggravates the extent of pulmonary hypertension, e.g., during acute bacterial infection in patients with chronic obstructive pulmonary disease. Experimental evidence suggests endothelial nitric oxide production as the main regulator ofvascular tone in pulmonary arteries. Nitric oxide (NO) is mainly produced by three isoforms of NO synthases (NOS 1-3), two of which are constitutively present in neuronal or endothelial cells (NOS-1 or NOS-3, respectively) (1). In human umbilical vein endothelial cells, hypoxia was found to be responsible for both a decrease of human NOS-3 and an increase of human endothelin 1 (ET-1) mRNA (2). Conversely, exposure of rat lungs to hypoxia for more than 1 week caused an increase of both NOS-3 mRNA and protein leading to a doubled production of NO (3). In short-term cultures using human aortic endothelial cells, inflammatory mediators have been demonstrated both to increase the mRNA of the inducible isoform of nitric oxide synthases (iNOS or NOS-2) and to decrease the amount of NOS-3 mRNA, which may imply a major influence of NOS-2 on the regulation of vascular tone during inflammatory states (4). NO has been shown to down-regulate the expression of vasoconstrictors and growth factors such as ET-1, interleukin 1 (IL-1), and platelet-derived growth factor in human umbilical vein endothelial cells (5). Similarly, proinflammatory cytokines were shown to induce the synthesis of NO, suggesting a crucial role of inflammatory mediators in the regulation of arterial tissues (6). Analogously, hypoxia stimulated the induction of major vascular growth factors such as ET-1 (5) and platelet-derived growth factor B (PDGF-B) (8). To evaluate the influence of inflammation and/or hypoxia on the regulation of NO biosynthesis, we characterized the...

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“…This exposure has previously been reported to produce severe neonatal pulmonary hypertension with characteristic hemodynamic and structural changes (13)(14)(15)(16)(17). Agematched controls were kept indoors at ambient altitude (1500 m, 640 mm Hg).…”

Section: Methodsmentioning

confidence: 99%

cAMP Response Element-binding Protein Content Is a Molecular Determinant of Smooth Muscle Cell Proliferation and Migration

Klemm¹,

Watson²,

Frid³

et al. 2001

Journal of Biological Chemistry

128

136

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We hypothesized that cAMP response element-binding protein (CREB) could function as a molecular determinant of smooth muscle cell fate. In arterial sections from the systemic and pulmonary circulation, CREB content was high in proliferation-resistant medial subpopulations of smooth muscle cells and low in proliferation-prone regions. In vessels from neonatal calves exposed to chronic hypoxia, CREB content was depleted and smooth muscle cell (SMC) proliferation was accelerated. Induction of quiescence by serum deprivation in culture led to increased CREB content. Highly proliferative SMC in culture were observed to have low CREB content. Exposure to proliferative stimuli such as hypoxia or platelet-derived growth factor decreased SMC CREB content. Assessment of CREB gene transcription by nuclear run-on analysis and transcription from a CREB promoter-luciferase construct indicate that CREB levels in SMC are in part controlled at the level of transcription. Overexpression of wild type or constitutively active CREB in primary cultures of SMC arrested cell cycle progression. Additionally, expression of constitutively active CREB decreased both proliferation and chemokinesis. Consistent with these functional properties, active CREB decreased the expression of multiple cell cycle regulatory genes, as well as genes encoding growth factors, growth factor receptors, and cytokines. Our data suggest a unique mode of cellular phenotype determination at the level of the nuclear content of CREB.The vessel wall, once seen as simply a mechanical conduit for blood flow, is a complex organ whose dysfunction is responsible for the leading cause of death in the United States, cardiovascular disease. The lumen of blood vessels is lined with endothelial cells, which communicate with the underlying medial cell layer. For many years, the arterial media was considered to be made-up of a homogeneous population of smooth muscle cells (SMC) 1 arising from a common lineage. Thus the diverse activities of contraction, proliferation, migration, and extracellular matrix production were thought to reflect SMC response to either normal or pathological stimuli. Vascular remodeling is the compensatory response of the vasculature to stress or injury. Under pathological circumstances (hypoxia, mechanical injury, hyperlipidemia, and oxidative stress), SMC in the intimal and medial compartments of the arterial wall become proliferative, migratory, and produce excess matrix proteins. This switch in SMC phenotype is termed phenotypic modulation and is considered to play a key pathogenic role in atherosclerosis and pulmonary hypertension. While the stimuli for SMC activation are well known, the molecular events, which permit activation of SMC, remain poorly understood.Cyclic nucleotides (cAMP and cGMP) promote SMC quiescence in vitro and in vivo. ␤-Adrenergic stimulation of cAMP signaling is important for SMC quiescence and contractile function under normal conditions. It is believed that cAMP acts as a gate to prevent SMC mitogenic response to growth fac...

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Persistence of the fetal pattern of tropoelastin gene expression in severe neonatal bovine pulmonary hypertension.

Cited by 41 publications

References 37 publications

Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension

Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension

Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue.

cAMP Response Element-binding Protein Content Is a Molecular Determinant of Smooth Muscle Cell Proliferation and Migration

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