Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is IntroductionPulmonary arterial hypertension (PAH) is a rare but fatal disease, often of unknown origin, characterized by progressive increase in pulmonary vascular resistance and remodeling associated with vasoconstriction. 1 PAH is histologically characterized by a neomuscularization of small pulmonary arteries with intimal thickening, medial hypertrophy, adventitial proliferation, and abnormal extracellular matrix deposition. The progression of vascular remodeling results in vascular lumen narrowing, increased pulmonary artery resistance, hypoxia, and right heart hypertrophy, although the molecular pathways initiating this remodeling are not clearly established.On the one hand, stem cells, resident or not, may give rise to a significant proportion of differentiating/proliferating smooth muscle cells (SMCs) that contribute to intimal hyperplasia in lung vascular remodeling. 2 Moreover, genetic ablation of the transmembrane tyrosine kinase receptor for stem cell factor/c-kit pathway results in a marked reduction in intimal hyperplasia in animal models of vascular injury; conversely, wild-type (WT) bone marrow (BM) reconstitution in c-kit mutant mice led to intimal hyperplasia comparable with WT animals. 3 Pharmacologic antagonism of the c-kit pathway with STI-571 (imatinib mesylate; Gleevec) also results in a marked reduction in hyperplasia. 3 Mobilization of c-kit expressing cells from BM to blood circulation is a physiologic response to hypoxia. Increasing evidence supports the idea that these progenitor cells of BM origin may also contribute to vascular wall remodeling that is characteristic of PAH. [4][5][6][7][8] However, it is unclear, whether this entry of progenitors represents a protective or a worsening process in the development of PAH. 9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH. 14 Therapeutic drugs with PAH as a side effect, such as the amphetamine derivative and anorexigen dexfenfluramine, are potent 5-HT releasers acting at 5-HT transporter (SERT) and/or agonists at 5-HT receptors (5-HTRs). 15 An over-expression of 5-HT 2B Rs is observed in PAH. 16 Blockade of 5-HT 2B Rs using independent approaches, either genetic (5-HT 2B R knock-out mice; 5-HT 2B Ϫ/Ϫ ) or pharmacologic (5-HT 2B antagonist RS-12744) inactivation, completely prevented the development of hypoxia-induced pulmonary hypertension in mice. 16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduc...

Serotonin Skews Human Macrophage Polarization through HTR2B and HTR7

“…Thus, the presence of 5HT 2B in lung macrophages, as well as its expression in human TAM, which promote tumor cell growth and dissemination, raises the question of whether 5HT 2B -positive macrophages might contribute to PAH by enhancing proliferation of other cell types (endothelium, smooth muscle) or through exacerbated extracellular matrix deposition. This possibility is compatible with the recent finding that PAH development requires the expression of the murine 5HT 2B receptor in bone marrow-derived progenitor cells (27).…”

“…Others have shown that 5HT is shuttled from dendritic cells to naive T lymphocytes as a means to modulate T cell activation, proliferation, and differentiation (24), and that it might be necessary for optimal macrophage accessory function (25). In the context of inflammatory pathologies, 5HT regulates macrophagemediated angiogenesis by reducing matrix metalloproteinase 12 (MMP12) expression in tumor-infiltrating macrophages (26), and its contribution to the development of pulmonary arterial hypertension depends on 5HT 2B receptor expression on bone marrow progenitors (27). Thus, 5HT modulates myeloid cell functions in a variable manner, and its effects are dependent on the profile of 5HT receptors expressed by each macrophage subtype.…”

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…The 5-HT 2B receptor has also been implicated in determining the fate of bone marrow lineage progenitor cells and their role in pulmonary vascular remodeling; mice with restricted elimination of the receptor in bone marrow cells were resistant to hypoxia or monocrotaline-induced pulmonary hypertension (J-M M Launay et al, 2012). However, unlike the 5-HT 1B receptor, there is currently no evidence that the 5-HT 2B receptor mediates vasoconstriction of human pulmonary arteries.…”

Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections

“…Integrating the participation of both microglia and 5-HT in segregation of eye-specific RGC projections, it was interesting to evaluate the putative participation of 5-HT 2B receptors since (i) peripheral macrophages have been shown to express 5-HT 2B receptors 25 ; (ii) the phenotype of mice lacking 5-HT 2B receptors includes neurodevelopmental-like disorders 26 . (iii) 5-HT 2B receptors have been implicated in exosome secretion by microglia 27 ; and (iv) 5-HT 2B receptors participate in hematopoietic precursors differentiation especially of the myeloid lineage 28 .…”