Transgenic Mice Overexpressing the 5-Hydroxytryptamine Transporter Gene in Smooth Muscle Develop Pulmonary Hypertension

Abstract

Abstract-One intrinsic abnormality of pulmonary artery smooth muscle cells (PA-SMCs) in human idiopathic pulmonary hypertension (iPH) is an exaggerated proliferative response to internalized serotonin (5-HT) caused by increased expression of the 5-HT transporter (5-HTT). To investigate whether 5-HTT overexpression in PA-SMCs is sufficient to produce PH, we generated transgenic mice overexpressing 5-HTT under the control of the SM22 promoter. Studies in SM22-LacZ ϩ mice showed that the transgene was expressed predominantly in SMCs of pulmonary and systemic vessels. Compared with wild-type mice, SM22-5-HTT ϩ mice exhibited a 3-to 4-fold increase in lung 5-HTT mRNA and protein, together with increased lung 5-HT uptake activity, but no changes in platelet 5-HTT activity or blood 5-HT levels. At 8 weeks of age, SM22-5-HTT ϩ mice exhibited PH, with marked increases in right ventricular systolic pressure (RVSP), right ventricle/left ventricleϩseptum ratio, and muscularization of distal pulmonary vessels, but no changes in systemic arterial pressure. PH worsened with age. Except a marked decrease in Kv channels, no changes in the lung expression of mediators of pulmonary vascular remodeling were observed in SM22-5-HTT ϩ mice. Compared with wild-type mice, SM22-5-HTT ϩ mice showed depressed hypoxic pulmonary vasoconstriction contrasting with greater severity of hypoxia-or monocrotaline-induced PH. These results show that increased 5-HTT expression in PA-SMCs, to a level close to that found in human iPH, lead to PH in mice.

Leptin signalling system as a target for pulmonary arterial hypertension therapy

“…Numerous preclinical studies support the beneficial effects of DCA against experimental PH, including in the chronic hypoxia-and monocrotaline-induced PH [28,[43][44][45][46]. DCA is known to target the cellular glycolysis/glucose oxidation ratio and to shift cell metabolism from anaerobic glycolysis to oxidative phosphorylation, via pyruvate dehydrogenase kinase inhibition, leading to HIF-1α degradation [27].…”

Potassium channels in pulmonary arterial hypertension

“…The implication that serotonin is a key determinant of vessel remodelling was further confirmed by several observations highlighting: 1) high platelet and plasma levels of serotonin in patients with PAH [22], 2) prevention of PAH in animal models following inhibition of serotonin receptors [23,24], and 3) a congenital predisposition to develop PAH in fawn-hooded rats caused by a defect in platelet serotonin storage [25]. Briefly, under pathological conditions, pulmonary endothelial cells produce high levels of serotonin that acts in a paracrine fashion on adjacent PASMCs to promote cell proliferation and contraction [26][27][28]. Results showing that exposure of human normotensive PASMCs to aminorex, fenfluramine or dexfenfluramide (appetite suppressant drugs that interact with the metabolism of serotonin) reduces the expression of K V 1.5 and inhibits K + current support the notion that serotonin signalling causes PAH, at least in part, through its effect on K V channel gene regulation [29,30].…”

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…In the disease state there is suppressed apoptosis, increased proliferation and muscularization of normally non-muscular distal and peripheral arteries (Humbert et al, 2004), creating a stiffened, noncompliant vessel. This phenotype is characterized by mutation or downregulation in bone morphologic protein receptor 2 (BMPR2), loss of voltage-gated potassium (Kv1.5) channels, metabolic abnormalities (Humbert et al, 2004), overexpression of serotonin transporter (5-HTT) (Guignabert et al, 2006), increased expression of various growth factors (Crosswhite et al, 2014) and impaired cross-talk with ECs.…”