Cellular Pathways Promoting Pulmonary Vascular Remodeling by Hypoxia

Shimoda, Larissa A.

doi:10.1152/physiol.00039.2019

Cited by 30 publications

(18 citation statements)

References 181 publications

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“…The increase in PAP observed in animal models of CSH is due to PA remodeling, as well as pro-contractile changes in pulmonary vascular smooth muscle cells such as membrane depolarization, the upregulation of non-voltage gated Ca 2+ entry pathways, and the enhancement of rho kinase- dependent Ca 2+ sensitization. The mechanisms inducing these changes include the activation of HIF 1a , HIF 2a , and mTORC [ 35 ], as well as increases in ROS production by NADPH oxidase and mitochondria, possibly acting in concert with a decrease in the [superoxide]/[H 2 O 2 ] ratio in the PA [ 36 ]. The increase in the baseline PAP caused by CSH is also generally seen as being dependent on an attenuation of NO-induced vasodilation together with an increased release of, and responsiveness to, ET-1 [ 37 , 38 ], although there have been reports that vasorelaxation via endothelial NO release is increased in animals subjected to CSH [ 34 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat

et al. 2021

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Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

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Section: Discussionmentioning

confidence: 99%

Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat

et al. 2021

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“…In the pathogenesis of pulmonary hypertension, conditions such as chronic hypoxia, activation of voltage-gated calcium channels, and extracellular calcium-sensing receptors contributed to vascular remodeling by promoting pulmonary arterial smooth muscle cell proliferation and retarding apoptosis of endothelial cells ( Smith et al, 2016 ; Xiao et al, 2017 ; Shimoda, 2020 ). p53, a master regulator of cell cycle arrest, apoptosis, cell proliferation and DNA repair etc., was found to crosstalk with hypoxia-inducible transcription factors.…”

Section: P53 and Vascular Remodeling In Pulmonary Hypertensionmentioning

confidence: 99%

The role of p53 in the alternation of vascular functions

Chan

Kwok

et al. 2022

Front. Pharmacol.

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Ageing is a risk factor for many degenerative diseases. Cardiovascular diseases (CVDs) are usually big burdens for elderly, caregivers and the health system. During the aging process, normal functions of vascular cells and tissue progressively lost and eventually develop vascular diseases. Endothelial dysfunction, reduced bioavailability of endothelium-derived nitric oxide are usual phenomena observed in patients with cardiovascular diseases. Myriad of studies have been done to investigate to delay the vascular dysfunction or improve the vascular function to prolong the aging process. Tumor suppressor gene p53, also a transcription factor, act as a gatekeeper to regulate a number of genes to maintain normal cell function including but not limited to cell proliferation, cell apoptosis. p53 also crosstalk with other key transcription factors like hypoxia-inducible factor 1 alpha that contribute to the progression of cardiovascular diseases. Therefore, in recent three decades, p53 has drawn scientists’ attention on its effects in vascular function. Though the role of tumor suppressor gene p53 is still not clear in vascular function, it is found to play regulatory roles and may involve in vascular remodeling, atherosclerosis or pulmonary hypertension. p53 may have a divergent role in endothelial and vascular muscle cells in those conditions. In this review, we describe the different effects of p53 in cardiovascular physiology. Further studies on the effects of endothelial cell-specific p53 deficiency on atherosclerotic plaque formation in common animal models are required before the therapeutic potential can be realized.

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“…It is principally characterized by medial thickening and increased muscularization of the pulmonary arteries due to enhanced migration and proliferation of pulmonary artery smooth muscle cells (PASMCs) [ 7 , 8 ]. Likewise, excessive migration and proliferation of PASMCs are the hallmark features of pulmonary vascular remodeling [ 9 ]. Therefore, it is critical to identify the underlying pathological mechanisms of PASMCs to prevent and treat of PH.…”

Section: Introductionmentioning

confidence: 99%

Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy

Chang

Jin

et al. 2022

Oxidative Medicine and Cellular Longevity

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Pulmonary hypertension (PH) is caused by chronic hypoxia that induces the migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), eventually resulting in right heart failure. PH has been related to aberrant autophagy; however, the hidden mechanisms are still unclear. Approximately 40% East Asians, equivalent to 8% of the universal population, carry a mutation in Aldehyde dehydrogenase 2 (ALDH2), which leads to the aggregation of noxious reactive aldehydes and increases the propensity of several diseases. Therefore, we explored the potential aspect of ALDH2 in autophagy associated with PH. In vitro mechanistic studies were conducted in human PASMCs (HPASMCs) after lentiviral ALDH2 knockdown and treatment with platelet-derived growth factor-BB (PDGF-BB). PH was induced in wild-type (WT) and ALDH2-knockout (ALDH2-/-) mice using vascular endothelial growth factor receptor inhibitor SU5416 under hypoxic conditions (HySU). Right ventricular function was assessed using echocardiography and invasive hemodynamic monitoring. Histological and immunohistochemical analyses were performed to evaluate pulmonary vascular remodeling. EdU, transwell, and wound healing assays were used to evaluate HPASMC migration and proliferation, and electron microscopy and immunohistochemical and immunoblot assays were performed to assess autophagy. The findings demonstrated that ALDH2 deficiency exacerbated right ventricular pressure, hypertrophy, fibrosis, and right heart failure resulting from HySU-induced PH. ALDH2-/- mice exhibited increased pulmonary artery muscularization and 4-hydroxynonenal (4-HNE) levels in lung tissues. ALDH2 knockdown increased PDGF-BB-induced PASMC migration and proliferation and 4-HNE accumulation in vitro. Additionally, ALDH2 deficiency increased the number of autophagosomes and autophagic lysosomes together with autophagic flux and ERK1/2-Beclin-1 activity in lung tissues and PASMCs, indicating enhanced autophagy. In conclusion, the study shows that ALDH2 has a protective role against the migration and proliferation of PASMCs and PH, possibly by regulating autophagy through the ERK1/2-Beclin-1 pathway.

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Cellular Pathways Promoting Pulmonary Vascular Remodeling by Hypoxia

Cited by 30 publications

References 181 publications

Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat

Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat

The role of p53 in the alternation of vascular functions

Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy

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