The role of neurotrophins in psychopathology and cardiovascular diseases: psychosomatic connections

Abstract

Cardiovascular (CV) diseases and mood disorders are common public health problems worldwide. Their connections are widely studied, and the role of neurotrophins (NTs) is already supposed in both conditions. However, data in the literature of clinical aspects are sometimes controversial and no reviews are available describing possible associations between CV risk and mood disorders based on NTs. The mostly studied NT is brain-derived neurotrophic factor (BDNF). Decreased level of BDNF is observed in depression and its connection to hypertension has also been demonstrated with affecting the arterial baroreceptors, renin-angiotensin system and endothelial nitric oxide synthase. BDNF was also found to be the predictor of CV outcome in different patient populations. Other types of human NT-s, such as nerve growth factor, neurotrophin 3 and neurotrophin 4 also seem to have both psychopathological and CV connections. Our aim was to overview the present knowledge in this area, demonstrating a new aspect of the associations between mood disorders and CV diseases through the mediation of NTs. These findings might enlighten new psychosomatic connections and suggest new therapeutic targets that are beneficial both in respect of mood disorders and CV pathology.

Keywords: Cardiovascular diseases; Mood disorders; Neurotrophic factors; Psychosomatic connections.

Fig. 1

Crossroads of neurotrophins in cardiovascular system and psychopathology. Neurotrophin family consists four types of neurotrophins (NTs): nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). NTs are synthesized as proforms that can be cleaved to release mature NTs. Both pro and mature forms of NTs are biologically active and eliciting opposite effects. ProNTs typically activate apoptotic downstream pathways via neurotrophin receptor p75 (p75Ntr). The effects of mature NTs are mediated by three tyrosine kinase receptors: NGF interacts with tropomyosin receptor kinase (Trk) A, BDNF binds to TrkB, NT-3 binds to TrkC and lower affinity to TrkA and TrkB (illustrated by gray dashed line) and NT-4 also interacts with TrkB. The effects of NTs on cardiovascular (CV) system: (i) NGF may have a protective role in atherosclerosis by upregulating LDL receptor-related protein (LPR) and increasing glucose-induced insulin secretion, while NT-4 and NT-3 seems to be a profibrotic mediator in aortic valve. (ii) Both BDNF and NGF promote angiogenesis through vascular endothelial cells directly or by influencing the action of other endogenous factors indirectly. (iii) BDNF is required for the survival of arterial baroreceptors. NT-3 is involved in the development of chemoafferent sensory neurons’ innervations of the carotid body. (iv) NGF promotes the survival of sympathetic and sensory neurons that innervate the heart. NT-3 promotes the development of the arteries and of the ventricles of the heart. The effects of NTs on mood disorders: (i) BDNF and NGF participate in the pathophysiology of depression: reduced levels of NGF and BDNF in serum and also in plasma have been demonstrated in patients suffering from depression. (ii) Association between mood disorders and NT-3, NT-4 is plausible, but results are still controversial (illustrated by dashed narrows). Renin–angiotensin system (RAS) is one of the possible pathways might explaining the association between BDNF and CV function and susceptibility to mental disorders