Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension.

West JD, Carrier EJ, Bloodworth NC, Schroer AK, Chen P, Ryzhova LM, Gladson S, Shay S, Hutcheson JD, Merryman WD
PLoS One. 2016 11 (2): e0148657

PMID: 26863209 · PMCID: PMC4749293 · DOI:10.1371/journal.pone.0148657

Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice.

MeSH Terms (24)

Animals Bone Morphogenetic Protein Receptors, Type II Cell Movement Cytoskeletal Proteins Gene Expression Profiling Gene Expression Regulation Hypertension, Pulmonary Indoles Lung Mice Mice, Transgenic Muscle Contraction Muscle Proteins Mutation Myocytes, Smooth Muscle Oligonucleotide Array Sequence Analysis Phosphorylation Protein Transport Receptor, Serotonin, 5-HT2B Serotonin Antagonists Signal Transduction src-Family Kinases Urea Vascular Stiffness

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