Transforming growth factor-β inhibition attenuates pulmonary arterial hypertension in rats

The role of transforming growth factor-β in the pathogenesis of pulmonary arterial hypertension is unclear. We examined the effects of T9429, an antibody against transforming growth factor-β receptors, on hemodynamic, histological and functional parameters in the rat model of monocrotaline-induced pulmonary hypertension. One week after monocrotaline injection (60 mg/kg) in 28 Wistar rats, T9429 (0.1mg/kg daily) was administered intraperito-neally in 19 rats (268±10g) via an osmotic mini-pump for 7 days. One week thereafter, right ventricular systolic pressure, pulmonary vascular remodeling and exercise tolerance were evaluated. Compared to the monocrotaline group (25.5±1.9mmHg), right ventricular systolic pressure was lower (p=0.0014) in the monocrotaline+antibody group (18.4±0.8mmHg). This was translated into attenuated right ventricular hypertrophy (p=0.0063) and longer (p=0.0155) exercise duration (2.08±0.29min versus 6.19±1.02min). Pulmonary arterial wall thickness (in vessels 50 -200μm) was comparable between the two groups, but the monocrotaline+antibody group displayed lower number (p<0.0001) of pre-capillary arterioles (<50μm, in 20 randomly selected fields) with a muscularized media (23.33±3.15 versus 6.64±0.75). Our results suggest that transforming growth factor-β receptor blockade improves vascular remodeling and attenuates pulmonary hypertension, a finding with potential therapeutic implications.