Contribution of the 5-HT
            <sub>1B</sub>
            Receptor to Hypoxia-Induced Pulmonary Hypertension

Keegan, Alan; Morecroft, Ian; Smillie, Diane; Hicks, Martin N.; MacLean, Margaret R.

doi:10.1161/hh2401.100426

Cited by 185 publications

(57 citation statements)

References 23 publications

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“…Smooth muscle cell proliferation is stimulated by serotonin binding and internalization by the transporter protein (23). The receptors for serotonin, 5-HT1B and 5-HT2B, have also been suggested to play a role in vascular smooth muscle cell proliferation in rodent models of pulmonary hypertension (22,24). We show that administration of fluoxetine, a serotonin transporter inhibitor, completely blocked the proliferative effect of serotonin released by endothelial cells treated with Ang-1.…”

Section: Discussionmentioning

confidence: 78%

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Sullivan

Li²,

Chu³

et al. 2003

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

142

105

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Smooth muscle cell proliferation around small pulmonary vessels is essential to the pathogenesis of pulmonary hypertension. Here we describe a molecular mechanism and animal model for this vascular pathology. Rodents engineered to express angiopoietin 1 (Ang-1) constitutively in the lung develop severe pulmonary hypertension. These animals manifest diffuse medial thickening in small pulmonary vessels, resulting from smooth muscle cell hyperplasia. This pathology is common to all forms of human pulmonary hypertension. We demonstrate that Ang-1 stimulates pulmonary arteriolar endothelial cells through a TIE2 (receptor with tyrosine kinase activity containing IgG-like loops and epidermal growth factor homology domains) pathway to produce and secrete serotonin (5-hydroxytryptamine), a potent smooth muscle mitogen, and find that high levels of serotonin are present both in human and rodent pulmonary hypertensive lung tissue. These results suggest that pulmonary hypertensive vasculopathy occurs through an Ang-1͞ TIE2͞serotonin paracrine pathway and imply that these signaling molecules may be targets for strategies to treat this disease.

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Section: Discussionmentioning

confidence: 78%

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Sullivan

Li²,

Chu³

et al. 2003

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

142

105

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“…15 In total, 133Ϯ29 wild-type and 110Ϯ16 5-HTTϩ vessels were counted per mouse lung section (nϭ5 to 6 lungs studied per group). Fully muscularized vessels with an external diameter Ͻ80 m were also analyzed by computerassisted imaging.…”

Section: Lung Histologymentioning

confidence: 99%

“…The percentage wall thickness was calculated as described previously. 15 Two to 4 vessels were analyzed per lung section, and the results were expressed as meanϮSEM (nϭ6 lungs studied per group).…”

Section: Lung Histologymentioning

confidence: 99%

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Overexpression of the 5-Hydroxytryptamine Transporter Gene

et al. 2004

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Background-Increased serotonin (5-hydroxytryptamine, 5-HT) transporter activity has been observed in human familial pulmonary hypertension. Methods and Results-We investigated pulmonary hemodynamics and the development of hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in mice overexpressing the gene for the 5-HT transporter (5-HTTϩ mice). Right ventricular pressure was elevated 3-fold in normoxic 5-HTTϩ mice compared with their wild-type controls. Hypoxia-induced increases in right ventricular hypertrophy and pulmonary vascular remodeling were also potentiated in the 5-HTTϩ mice. 5-HTT-like immunoreactivity, protein, and binding sites were markedly increased in the lungs from the 5-HTTϩ mice. Hypoxia, however, decreased 5-HT transporter immunoreactivity, mRNA transcription, protein, and binding sites in both wild-type and 5-HTTϩ mice. Conclusions-Increased

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“…Conversely, increased 5-HTT expression was associated with increased severity of hypoxic PH [50]. Although a heterogeneous population of 5-HT2A and 5-HT1B receptors exist in pulmonary arteries, 5-HT receptor antagonists do not seem as efficient as 5-HTT inhibitors in protecting against the development of hypoxic PH [51,52]. Taken together, these observations suggest a close correlation between 5-HTT expression and/or activity and the extent of pulmonary vascular remodelling during exposure to hypoxia.…”

Section: Pathobiological Mechanisms and Candidate Genesmentioning

confidence: 99%

Pathobiology of pulmonary arterial hypertension

Eddahibi

Morrell²,

d’Ortho³

et al. 2002

Eur Respir J

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Recent years have witnessed important advances in the understanding of the pathophysiology of primary pulmonary hypertension (PPH). Both genetic and mechanistic studies have succeeded in identifying new molecular pathways relevant to the process of pulmonary vascular remodelling, which underlies PPH.Mutations in the type II bone morphogenetic protein (BMP) receptor (BMPR)-II are now considered to be the genetic basis for familial PPH and y30% of cases of sporadic PPH. The identification of the relevance of the BMP pathway to the aetiology of PPH now raises many questions about the link between the BMPR-II mutant genotype and the PPH phenotype.As PPH does not develop in all subjects with BMPR-II mutations, environmental or associated genetic factors may play a crucial role. Among these, the finding of an association between PPH and the L-allelic variant of the serotonin transporter (5-HTT) gene indicates that 5-HTT, which controls smooth muscle hyperplasia, probably contributes to susceptibility to PPH or is an important modifier of the PPH phenotype.Recognition of these molecular pathways should provide insight into the pathogenesis not only of primary pulmonary hypertension, but also of secondary forms of pulmonary hypertension. This should soon lead to the development of new and more selective therapeutic approaches to pulmonary hypertension.

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Contribution of the 5-HT _1B Receptor to Hypoxia-Induced Pulmonary Hypertension

Cited by 185 publications

References 23 publications

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Overexpression of the 5-Hydroxytryptamine Transporter Gene

Pathobiology of pulmonary arterial hypertension

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Contribution of the 5-HT 1B Receptor to Hypoxia-Induced Pulmonary Hypertension

Cited by 185 publications

References 23 publications

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Overexpression of the 5-Hydroxytryptamine Transporter Gene

Pathobiology of pulmonary arterial hypertension

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Contribution of the 5-HT _1B Receptor to Hypoxia-Induced Pulmonary Hypertension