Regulation of the Pulmonary Circulation in the Fetus and Newborn

Gao, Yuansheng; Raj, J. Usha

doi:10.1152/physrev.00032.2009

Cited by 290 publications

(286 citation statements)

References 638 publications

(744 reference statements)

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“…The third important pathway involves prostaglandins and thromboxanes that act on prostanoid receptors which can be divided in receptors that cause relaxation (IP (PTGIR), EP2, EP4 and DP) or contraction (TP, EP1 and FP) of the pulmonary vessels to change the vascular tone [14]. PGI 2 is an important mediator of vasodilation which binds and activates the prostaglandin-I 2 receptor (PTGIR) [15,16]. This activation results in vasodilation through the release of cAMP.…”

mentioning

confidence: 99%

Pulmonary vascular development in congenital diaphragmatic hernia

et al. 2018

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Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality. Normal pulmonary vascular developmentHuman lung development can be divided into different stages based on histology, starting with the embryonic stage at 4 weeks of gestation, followed by the pseudoglandular stage in which branching of the lung buds continues. During the canalicular stage, starting at ∼16 weeks of gestation, the terminal bronchioli are formed. From 24 weeks of gestation until term, the saccular stage, airspaces widen and alveoli are formed. During the alveolar stage, which persists into the postnatal period up to 3 years of age, maturation of the airways occurs [1]. Concomitant with the expansion of the airways is the adaptation of the microvasculature to optimise the exchange of oxygen and carbon dioxide between the blood and the airways. We and others have shown that very early in lung development pulmonary vessels are present and connected to the systemic circulation. The vasculature develops in close relation with the airways and is a rate-limiting factor in branching morphogenesis [2][3][4]. This implies that the pulmonary vasculature plays an important role in lung development. The formation of new blood vessels primarily occurs through

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confidence: 99%

Pulmonary vascular development in congenital diaphragmatic hernia

et al. 2018

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“…In contrast, sGCb1 expression in the kidney and heart of the mouse was not affected by hypoxia. It suggests that hypoxia-induced downregulation of sGC is specific for the lungs, and such an effect may in part contribute to hypoxic pulmonary vasoconstriction (Gao and Raj, 2010;Sylvester et al, 2012). It is of interest to note that in our in vivo study the protein levels of sGCb 1 in the lungs were reduced after the mice were exposed to hypoxia of 8% O 2 for 72 hours.…”

Section: Sp1 Mediates Hypoxia-induced Upregulation Of Mir-34c-5p In Mmentioning

confidence: 75%

Hypoxia induces downregulation of soluble guanylyl cyclase β1 by miR-34c-5p

Wang

Liu

et al. 2012

Journal of Cell Science

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SummarySoluble guanylyl cyclase (sGC) is the principal receptor for nitric oxide (NO) and crucial for the control of various physiological functions. The b 1 subunit of sGC is obligatory for the biological stability and activity of the sGC heterodimer. MicroRNAs (miRNAs) are important regulators of gene expression and exert great influences on diverse biological activities. The aim of the present study was to determine whether or not the expression of sGCb 1 is specifically regulated by miRNAs. We report that miR-34c-5p directly targets sGCb 1 under hypoxia. Bioinformatics analysis of the sGCb 1 39-untranslated region (39-UTR) revealed a putative binding site for miR34b-5p and miR-34c-5p, but only miR-34c-5p inhibited luciferase activity through interaction with sGCb 1 39-UTR in HEK293T cells. Site-directed mutagenesis of the putative miR-34c-5p binding site abolished the negative regulation of luciferase expression. Overexpression of miR-34c-5p repressed the expression of sGCb 1 in stable cell lines, which was reversed by miR-34c-5p-specific sponge. Inoculation of mouse lung tissues in vitro with lentivirus bearing miR-34c-5p significantly decreased both the expression of sGCb 1 and NO-stimulated sGC activity, which was also rescued by miR-34c-5p-specific sponge. Furthermore, we identified the putative Sp1-binding site in the promoter region of miR-34c-5p. Luciferase reporter constructs revealed that Sp1 directly binds to the wild-type promoter of miR-34c-5p, which was confirmed by chromatin immunoprecipitation. In summary, these findings reveal that miR-34c-5p directly regulates sGCb 1 expression, and they identify the key transcription factor Sp1 that governs miR-34c-5p expression during hypoxia.

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“…EDNO can diffuse readily into the underlying SMCs to activate soluble guanylyl cyclase (sGC), resulting in increased production of cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG). The cyclic GMP-PKG pathway is the primary mechanism responsible for a broad range of the biological actions of EDNO (3). EDNO may cause pulmonary vasculature to relax by decreasing the cytosolic Ca 21 level resulting from PKG-dependent stimulation of Ca 21 -activated potassium channels, which leads to membrane hyperpolarization and Ca 21 influx suppression (25).…”

Section: Edno As a Paracrine Regulatormentioning

confidence: 99%

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Gao

Chen

Raj

2016

Am J Respir Cell Mol Biol

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In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, other mechanisms exist by which there is cross-talk between these two cell types, including communication via the myoendothelial injunctions and information transfer via extracellular vesicles. Emerging evidence suggests that these nonparacrine mechanisms play an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension.Keywords: paracrine; myoendothelial injunction; microvesicles; vasoconstriction; vascular remodelingIn the pulmonary vasculature, endothelial cells (ECs) and smooth muscle cells (SMCs) are the key cell types involved in the regulation of vessel diameter in most of the pulmonary vascular tree and thereby they regulate pulmonary arterial pressure and total vascular resistance. ECs, which are strategically located as the innermost layer of the blood vessel and are in contact with the circulating blood, exert a delicate and constant influence on the underlying vascular smooth muscle cells (VSMCs). It is well recognized that the regulation of pulmonary vasoreactivity by the endothelium is predominantly accomplished by paracrine signaling through the release of various vasoactive agents such as nitric oxide (NO), endothelin-1 (ET-1) (1-3), and others (4-8). However, there is increasing evidence that the relationship between the EC and the SMC is not a simple one-way interaction from the endothelium to the SMC; rather, there are complicated interactions between them (9-11). Moreover, the communication patterns are not limited to paracrine signaling; cross-talk through myoendothelial gap junctions (MEJs), extracellular vesicles (EVs), and other mechanisms is critically involved (12)(13)(14)(15)(16)(17)(18)(19)(20). These mechanisms operate in a complicated but co-ordinated manner to maintain the homeostasis of the pulmonary circulation. Under pathological conditions, the interaction between ECs and VSMCs may be chronically altered so that a sustained increase in vasocontractility and abnormal vascular proliferation develops, which leads to high pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and the clinical condition, pulmonary hypertension (PH) (1,(21)(22)(23)(24). This article discusses the recent progress in our knowledge of the interactions between ECs and SMCs thr...

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Regulation of the Pulmonary Circulation in the Fetus and Newborn

Cited by 290 publications

References 638 publications

Pulmonary vascular development in congenital diaphragmatic hernia

Pulmonary vascular development in congenital diaphragmatic hernia

Hypoxia induces downregulation of soluble guanylyl cyclase β1 by miR-34c-5p

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

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