Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice.

Pulmonary hypertension (PH) complicating bronchopulmonary dysplasia (BPD) worsens clinical outcomes in former preterm infants. Increased serotonin (5-hydroxytryptamine, 5-HT) signaling plays a prominent role in PH pathogenesis and progression in adults. We hypothesized that increased 5-HT signaling contributes to the pathogenesis of neonatal PH complicating BPD and neonatal lung injury. Thus, we interrogated 5-HT signaling in neonatal mice exposed to bleomycin, previously demonstrated to induce PH and alveolar simplification. Newborn wild-type (WT) mice received intraperitoneal PBS, ketanserin (1mg/kg), bleomycin (3 units/kg) or bleomycin (3 units/kg) + ketanserin (1mg/kg), three times weekly for three weeks. Following treatment with bleomycin pulmonary expression of the rate-limiting enzyme of 5-HT synthesis, tryptophan hydroxylase 1 (Tph1), was significantly increased. Bleomycin did not affect pulmonary 5-HT 2A receptor (R) expression, but did increase pulmonary gene expression of the 5-HT 2B R and serotonin transporter. Treatment with ketanserin, attenuated bleomycin induced PH (increased RVSP and RVH) and pulmonary vascular remodeling (decreased vessel density and increased muscularization of small vessels). In addition, we found that treatment with ketanserin activated pulmonary MAPK and Akt signaling in mice exposed to bleomycin. We conclude that 5-HT signaling is increased in a murine model of neonatal PH and pharmacologic inhibition of the 5-HT 2A R protects against the development of PH in neonatal lung injury. We speculate this occurs through restoration of MAPK signaling and increased Akt signaling.