Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension.

Morrell, Nicholas W.; Atochina, Elena N.; Danilov, Sergei M.; Stenmark, Kurt R.

doi:10.1172/jci118228

Cited by 190 publications

(136 citation statements)

References 37 publications

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“…To measure the extent of RVH, the heart was removed and the right ventricule (RV) free wall was dissected from the left ventricle plus septum (LV+S), and weighed separately (43). The degree of RVH was determined from the ratio RV/LV+S.…”

Section: Methodsmentioning

confidence: 99%

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

Cowburn

Crosby

Macías

et al. 2016

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

157

158

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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.A lveolar hypoxia affects vascular flow in the pulmonary vascular bed via an immediate vasoconstrictor response (hypoxic pulmonary vasoconstriction, or HPV) (1). This reduces perfusion of regions of the lung with lowered levels of airflow (2). In conditions including chronic obstructive pulmonary disease (3), idiopathic pulmonary fibrosis (4), and at high altitude (5), HPV probably contributes to persistent increases in pulmonary arterial pressures. This in turn is correlated with reduced plasticity of the vascular bed, sustained pulmonary vascular remodeling, and, ultimately, debilitating right ventricular hypertrophy (RVH) and failure (2).The hypoxia-inducible factors (HIFs) are transcription factors and key regulators of the molecular response to hypoxia. The targets of HIFs include genes controlling vascularization, cellular proliferation, migration, and metabolism (6-11). A wellcharacterized animal model of hypoxia-induced pulmonary hypertension involves exposure to chronic hypoxia (CH), typically 10-12% inspired oxygen. This results in extensive vascular remodeling, marked pulmonary hypertension and RVH over a period of a few weeks. Exposure to CH in rodents results in vasoconstriction and a pattern of vascular remodeling that is reminiscent of humans with hypoxia-associated pulmonary hypertension (12, 13).Mice that are hemizygous for either of the HIF isoforms, HIF-1α (14) or HIF-2α (15), have been shown to have attenuated pulmonary vascular remodeling following experimental CH. Conditional de...

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Section: Methodsmentioning

confidence: 99%

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

Cowburn

Crosby

Macías

et al. 2016

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

157

158

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“…Circulating All levels have been reported to increase during the first week of exposure to hypoxia but thereafter decline to baseline (Zakheim et al, 1976). Several early studies indicated that whole lung ACE activity is reduced by chronic exposure to hypoxia (Keane et al, 1982;Kay et al, 1985;Jederlinic et al, 1988), but recently a local increase in ACE levels has been observed in the walls of newly muscularized pulmonary arteries in hypoxic rat lung (Morrell et al, 1995a). Treatment with ACE inhibitors has been reported to reduce pulmonary arterial pressure and remodelling the right ventricular hypertrophy in the chronically hypoxic rat (Zakheim et al, 1975;Clozel et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung

Zhao¹,

Al-Tubuly²,

Sebkhi³

et al. 1996

British J Pharmacology

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“…Since angiotensin II is an important mediator of vasocostriction and vascular cell growth, local expression of vascular angiotensin converting enzyme (ACE) and angiotensin II AT1 and AT2 receptors may be associated with the development of hypoxic pulmonary hypertension. Marked longitudinal variation in ACE expression along the normal pulmonary vasculature was demonstrated, with the highest levels found in small muscular arteries associated with terminal and respiratory bronchioles [31]. Increased expression of ACE was detected in the endothelium or wall of small muscular arteries in an animal model of hypoxic pulmonary hypertension and clinical cases with primary and secondary pulmonary hypertension [31,32].…”

Section: Discussionmentioning

confidence: 98%

“…Marked longitudinal variation in ACE expression along the normal pulmonary vasculature was demonstrated, with the highest levels found in small muscular arteries associated with terminal and respiratory bronchioles [31]. Increased expression of ACE was detected in the endothelium or wall of small muscular arteries in an animal model of hypoxic pulmonary hypertension and clinical cases with primary and secondary pulmonary hypertension [31,32]. In addition, chronic hypoxia-induced distal muscularization is associated with significant increases in the expression of AT1 and AT2 receptors in a rat experimental model [33].…”

Section: Discussionmentioning

confidence: 99%

Discrepant distribution of big endothelin (ET)-1 and ET receptors in the pulmonary artery

et al. 2001

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Since pulmonary vasculature is complex in terms of regional difference in structure and function, it is important to understand the site of endothelin (ET) synthesis and the distribution of the ET system along the axial pathways of pulmonary artery.The expression of big ET-1, ET converting enzyme (ECE) and ETA receptors were examined in rat pulmonary arteries under normal and hypoxic conditions using an immunohistochemical method and Northern blot analysis.In normal conditions, big ET-1 was expressed in the intima and media of pulmonary arteries with a predominant distribution in the distal segments and a preferential localization in the media, while ETA receptors were dominantly expressed in the proximal segments. ECE was constitutively expressed in the intima and media. Following exposure to hypoxia, messenger ribonucleic acid (mRNA) expression of ET-1 and ETA receptors were up-regulated by two-fold and immunoreactivities for big ET-1, ECE, and ETA receptors significantly increased by two to five-fold in the distal segments.Smooth muscle cells are an important source of endothelin-1 in the pulmonary artery. The distribution of big endothelin-1 and endothelin A receptors in pulmonary arteries was discrepant in normal conditions while their expression concomitantly increased in the distal segments in hypoxic conditions. This heterogeneity may play an important role in the regulation of pulmonary vascular tone. Endothelins (ETs) and their receptors are abundantly expressed in the lung and postulated to play an important role in the regulation of pulmonary vascular tone. ET-l, a potent vasoconstrictor and smooth muscle mitogen composed of 21 amino acids, is synthesized from big ET-l by a specific cleavage at Trp 21 -Val 22 by ET converting enzyme (ECE) [l, 2]. The actions of ET-l are mediated by two different receptors, ETA and ETB receptors [1,2]. ETA receptors are found in pulmonary vascular smooth muscle cells and mediate smooth muscle contraction and the proliferation of smooth muscle cells and fibroblasts, while ETB receptors are expressed in endothelial cells (ETB1 receptors) and smooth muscle cells (ETB2 receptors) and cause either relaxation or contraction, respectively [2,3,4]. Since the pulmonary vascular bed is complex in terms of regional differences in both structure and function, it is important to know about localization and distribution of ET-1 and ET receptors. Although it is known that ET-1 is expressed in various cells including endothelial cells, epithelial cells, smooth muscle cells, and tissue macrophages in the lung [2,5,6], there are few studies showing the distribution of ET-1 and ECE expression along the axial pathways of the pulmonary artery.The over-expression of the messenger ribonucleic acid (mRNA) for ET-1, ETA and ETB receptors, and the overproduction of the ET-1 peptide in whole lung have been demonstrated in an experimental model of hypoxic pulmonary hypertension [6 -11]. Furthermore, blocking ETA receptors with selective antagonists attenuates the rise in pulmonary arte...

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Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension.

Cited by 190 publications

References 37 publications

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

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

Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung

Discrepant distribution of big endothelin (ET)-1 and ET receptors in the pulmonary artery

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