Rolle des Wachstumsfaktors BDNF (brain - derived neurotrophic factor) in der Hypoxie - induzierten Pulmonalen Hypertonie und Rechtsherzhypertrophie im Mausmodell
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Beschreibung
Pulmonary hypertension (PH) is defined by elevation of pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), with pre - capillary forms of PH also characterized by vascular remodeling of pulmonary vessels. Long lasting elevation of pulmonary pressure causes an increase in right ventricular (RV) afterload, which results in right heart hypertrophy and finally right heart failure. PH remains an incurable disease and available therapies can only delay the progression of PH. Currently, lung transplantation is the only therapeutic option for patients with severe PH.
The mechanisms underlying the pathognomonic vascular remodeling has not yet been fully elucidated. An imbalance between anti-apoptotic and pro-proliferative factors is suggested to play a key role in the development of pulmonary vascular remodeling in PH. Recent studies in the PH field, are focused on various growth factors, which activates tyrosine kinases. Elevated levels of a growth factor called brain - derived neurotrophic factor (BDNF), mostly known for its effect in the central nervous system where it regulates neuronal growth, differentiation and survival of neurons, were found in pulmonary vessels of PH patients. In addition, it has been shown that BDNF can be released from human pulmonary artery smooth muscle cells (PASMC) in vitro, and that this growth factor also regulates the PASMC proliferation. Against this background, the aim of this study was to clarify the role of BDNF in the pathogenesis of PH and right heart hypertrophy.
First, in vitro experiments were performed on isolated mouse PASMC. In the study, the pro-proliferative effect of BDNF found in human PASMC was confirmed in mouse PASMC. In addition, the mRNA expression of BDNF as well as high-affinity tyrosine kinase receptor (tyrosine kinase receptor B, TrkB) was found to be up - regulated in mouse PASMC after hypoxia exposure (1 % oxygen). The release of the BDNF protein was also significantly increased after hypoxia exposure, indicating that BDNF-TrkB signaling pathway is a possible key factor in the progression of vascular remodeling in PH.
Next, the role of the BDNF - TrkB signaling pathway was further evaluated in the hypoxic mouse model of PH by exposing mice to hypoxia (10 % O2) for four weeks. The chronic hypoxia mouse model of PH is known to be manifested by pathognomonic changes, similar to human PH. Since homozygous BDNF knockout is lethal, the smooth muscle cell (SMC) - specific BDNF knockout induced by tamoxifen was used. The hemodynamic parameters, right ventricular remodeling and pulmonary vascular remodeling were not significantly changed in the inducible SMC - specific BDNF knockout mice after four - week exposure to hypoxia, as compared to the non-BDNF - deficient control groups. Nevertheless, the SMC - specific BDNF knockout mice showed reduced right ventricular dilatation (RVID) and improved right ventricular systolic function (TAPSE), compared to the non - BDNF - deficient control groups after hypoxic exposure. All other echocardiographic parameters showed the same pattern in all genotypes. The obtained results indicate that the SMC - BDNF knockout has an impact on cardiac neural activity.
In order to examine the maximum effects of BDNF deficiency in the right heart, heterozygous BDNF knockout mice (BDNF+/-) and their littermates were subjected to pulmonary artery banding (PAB). Application of a metal clip around the pulmonary artery resulted in an increase in the right ventricle afterload, thus enabling the investigation of right heart hypertrophy independently of the pulmonary circulation as well as the hypoxic stimulus. The hemodynamic measurements showed that the morphological parameters of right heart hypertrophy and fibrosis in the right ventricle were not significantly different between the two experimental groups. In addition, there were no changes in mRNA expression level in the right ventricle of extracellular matrix proteins, such as collagen - 1, - 3, MMP - 2, and TIMP - 2, as well as the cardiac markers, ANP and BNP, between groups three weeks after PAB. However, BDNF+/- mice showed decreased right ventricular dilatation in echocardiographic follow - up three weeks after PAB surgery compared to wildtype controls, which is in line with the results obtained from the chronic hypoxia model.
In addition, plasma levels of BDNF were determined in PH and non - PH patients, and correlated with invasive hemodynamic parameters. The BDNF concentration showed a significant negative correlation with mPAP and PVR, indicating that low BDNF plasma concentrations could be associated with severe PH. In general, there was a significant difference between the analyzed groups of PH patients (control group versus pre - capillary or pre - / post - capillary group).
In conclusion:
1) BDNF increases PASMC proliferation in vitro, however, in vivo BDNF specific-SMC knockout did not counteract the chronic hypoxia - induced vascular remodeling in the mouse hypoxia model of PH. Presumably, BDNF released from other cell types might has an impact on the PASMC proliferation.
2) BDNF deficiency is protective against right ventricular dilatation in both chronic hypoxia and PAB model, suggesting the involvement of systemic factors (altered sympathetic activation).
3) The lower BDNF plasma level in PH patients correlates with the severity of the disease. Further studies are needed to define the role of BDNF in vascular remodeling and right heart failure as well as its relevance as a potential PH biomarker.
Autor*in
Katharina Schäfer
Themen in »Rolle des Wachstumsfaktors BDNF (brain - derived neurotrophic factor) in der Hypoxie - induzierten Pulmonalen Hypertonie und Rechtsherzhypertrophie im Mausmodell«
BDNF Hypoxie Pulmonale Hypertonie