Growth factors, such as the brain-derived neurotropic factor (BDNF) may be involved in development of pulmonary hypertension (PH) and right ventricular (RV) failure. BDNF caused proliferation of human pulmonary arterial smooth muscle cells (SMC) in vitro and was decreased in plasma of patients with left ventricular failure. We thus investigated the role of BDNF in patients with PH and mouse models of PH or isolated RV failure.
BDNF concentration was measured in plasma samples of PH patients and correlated to invasive hemodynamic measurements. Mice with inducible knockout of BDNF specifically in SMCs (SMC-BDNF-/-) were exposed for 4 weeks to hypoxia for induction of PH. Heterozygous knockout mice for BDNF (BDNF+/-) were subjected to pulmonary arterial banding (PAB) for induction of isolated RV pressure overload.
BDNF concentration negatively correlated with pulmonary vascular resistance (r2=0.304; p=0.006), but not cardiac index in PH patients. However, SMC-BDNF-/- showed similar pulmonary vascular remodeling and PH after hypoxic exposure compared to WT mice. The lack of effect in SMC-BDNF-/- mice may be due to adaptive responses, as in vitro BNDF release was only temporary increased in pulmonary arterial SMC after hypoxic exposure and its downstream receptor tropomyosin receptor kinase B (TrkB) was increased in pulmonary arterial SMC-BDNF-/- SMCs. Surprisingly, the RV was less dilated in hypoxic SMC-BDNF-/- and BDNF+/- after PAB, although cardiac output was not different compared to wild type mice.
In conclusion decreased BDNF plasma levels of PH patients may be an adaptive response to PH. The value of BDNF as biomarker for PH has to be further evaluated.