Serotonin Increases Susceptibility to Pulmonary Hypertension in BMPR2 -Deficient Mice

Abstract

Abstract-Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II (BMPR-II) receptor underlie the majority (Ͼ70%) of cases of familial pulmonary arterial hypertension (FPAH), and dysfunction of BMP signaling has been implicated in other forms of PAH. The reduced disease gene penetrance in FPAH indicates that other genetic and/or environmental factors may also be required for the clinical manifestation of disease. Of these, the serotonin pathway has been implicated as a major factor in PAH pathogenesis. We investigated the pulmonary circulation of mice deficient in BMPR-II (BMPR2 ϩ/Ϫ mice) and show that pulmonary hemodynamics and vascular morphometry of BMPR2 ϩ/Ϫ mice were similar to wild-type littermate controls under normoxic or chronic hypoxic (2-to 3-week) conditions. However, chronic infusion of serotonin caused increased pulmonary artery systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling in BMPR2 ϩ/Ϫ mice compared with wild-type littermates, an effect that was exaggerated under hypoxic conditions. In addition, pulmonary, but not systemic, resistance arteries from BMPR2 ϩ/Ϫ mice exhibited increased contractile responses to serotonin mediated by both 5-HT 2 and 5-HT 1 receptors. Furthermore, pulmonary artery smooth muscle cells from BMPR2 ϩ/Ϫ mice exhibited a heightened DNA synthesis and activation of extracellular signal-regulated kinase 1/2 in response to serotonin compared with wild-type cells. In vitro and in vivo experiments suggested that serotonin inhibits BMP signaling via Smad proteins and the expression of BMP responsive genes. These findings provide the first evidence for an interaction between BMPR-II-mediated signaling and the serotonin pathway, perturbation of which may be critical to the pathogenesis of PAH. Key Words: pulmonary arterial hypertension Ⅲ bone morphogenetic protein Ⅲ serotonin I diopathic pulmonary arterial hypertension (IPAH) is characterized by narrowing and obliteration of the small arteries of the lung leading to increased pulmonary vascular resistance. 1 Elevation of pulmonary arterial pressure leads to right ventricular failure. Patients present with dyspnea after exertion, and many died of right heart failure within 3 years of diagnosis, before modern therapies. 2 Treatment with prostanoids or endothelin receptor antagonists improves symptoms and survival, although, for many, the long-term outlook remains poor.Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II) occur in up to 70% of cases of familial PAH (FPAH). 3,4 Similar mutations were found in up to 26% of cases of idiopathic PAH. 5 However, the low disease gene penetrance suggests that other genetic or environmental factors are necessary to manifest clinical disease.A series of studies have implicated serotonin (or 5-HT) as a key mediator of PAH. 6 -8 For example, treatment of rats with serotonin potentiates the effects of hypoxia on pulmonary arterial pressure, right ventricular hypertrophy an...

Molecular pathogenesis of pulmonary arterial hypertension

“…Given the functional significance of BMPR2 signaling, it is not surprising that penetrance of the mutation appears to depend on the level of production of BMPR2 from the normal allele (30). Conversely, haploinsufficiency of BMPR2 (65), or even expression of dominant-negative BMPR2 in SMCs (66), in mice requires addition of other stimuli to bring out a more severe PAH phenotype (67).…”

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

“…Mice with deletion of BMPR2 in ECs (11) develop PAH, as do mice expressing a dominant-negative Bmpr2 gene after birth in vascular SMCs (12). Mice heterozygous for BMPR2 develop exaggerated PAH in response to hypoxia and serotonin (13). Reduced BMPR2 expression also occurs in monocrotaline (14) and chronic hypoxic (15) rat models of PAH, and delivery of BMPR2 by intravenous gene therapy attenuates the disease in both models (16,17).…”

Mitogen-Activated Protein Kinase Phosphatase-1 Is a Key Regulator of Hypoxia-Induced Vascular Endothelial Growth Factor Expression and Vessel Density in Lung

“…[27][28][29] Briefly, lung sections were stained with ␣SMA antibody and lightly counterstained with hematoxylin. The number of ␣SMA-positive vessels [between 10 and 50 m outside diameter (OD)] and alveoli were counted in ␣SMA-stained sections by an investigator who was unaware of the experimental conditions; 5 to 12 vessels were counted in each of the three lobes of lung in every animal.…”