Endothelial Brain-derived Neurotrophic Factor Research Articles

Endothelial cells are an important source of BDNF in rat skeletal muscle

BDNF (brain-derived neurotrophic factor) is present in skeletal muscle, controlling muscular metabolism, strength and regeneration processes. However, there is no consensus on BDNF cellular source. Furthermore, while endothelial tissue expresses BDNF in large amount, whether endothelial cells inside muscle expressed BDNF has never been explored. The aim of the present study was to provide a comprehensive analysis of BDNF localization in rat skeletal muscle. Cellular localization of BDNF and activated Tropomyosin-related kinase B (TrkB) receptors was studied by immunohistochemical analysis on soleus (SOL) and gastrocnemius (GAS). BDNF and activated TrkB levels were also measured in muscle homogenates using Western blot analysis and/or Elisa tests. The results revealed BDNF immunostaining in all cell types examined with a prominent staining in endothelial cells and a stronger staining in type II than type I muscular fibers. Endothelial cells but not other cells displayed easily detectable activated TrkB receptor expression. Levels of BDNF and activated TrkB receptors were higher in SOL than GAS. In conclusion, endothelial cells are an important and still unexplored source of BDNF present in skeletal muscle. Endothelial BDNF expression likely explains why oxidative muscle exhibits higher BDNF levels than glycolytic muscle despite higher the BDNF expression by type II fibers.

Endothelial TrkB receptor activation controls vascular tone of rat middle cerebral artery

Little is known on the cerebrovascular BDNF (brain-derived neurotrophic factor)/TrkB (tropomyosin related kinase B) pathway. This study investigated the contribution of endogenous endothelial BDNF to the control of vascular tone of rat middle cerebral artery (MCA) and the capacity of exogenous agonist of TrkB receptors to induce their relaxation. Endothelial cells constitutively expressed both BDNF and activated TrkB receptors. Supporting endothelial BDNF as an autocrine regulator of basal myogenic tone, incubation of MCA with the TrkB antagonist cyclotraxin B induced contraction as observed with incubation in the presence of inhibitors of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) production. Exposure of MCA with the TrkB agonist LM22A-4 that increased expression of TrkB receptors phosphorylated at tyrosine 816 induced relaxation of preconstricted MCA (EC50 6.7 × 10−8 mol/L) as efficiently than acetylcholine (EC50 5.3 × 10−8 mol/L). Finally, endothelium removal, exposure to a TrkB antagonist or to inhibitors of NO and EDHF production prevented the relaxant effect of LM22A-4. In conclusion, our study identified endothelial BDNF as a new autocrine regulator of vascular tone of MCA, thus making the endothelial BDNF/TrkB pathway an attractive target for strategies aiming to improve blood supply to the brain.

Brain-derived neurotrophic factor is a full endothelium-derived factor in rats

Most of what is known on vascular brain-derived neurotrophic factor (BDNF) derived from experiments on cultured endothelial cells. Therefore, the present study compared BDNF levels/localization in artery (aorta) vs vein (vena cava) from a same territory in rats either sedentary (SED) or exposed to treadmill exercise (EX) as a mean to stimulate endogenous endothelial nitric oxide (NO) production. In SED rats, for both artery and vein, BDNF was strongly expressed by endothelial cells, while only a faint and scattered expression was observed throughout the media. Endothelial and muscular BDNF staining as vascular BDNF protein levels were however higher in artery than in vein, while BDNF mRNA levels did not differ between vessels. Irrespective of the vessels, EX resulted in an increase (+50%) in BDNF protein levels with no change in BDNF mRNA levels, a selective endothelial BDNF overexpression (x4) and an increase in vascular levels of tropomyosin related kinase B receptors (TrkB) phosphorylated at tyrosine 816 (p-TrkBTyr816). Endothelial expressions of BDNF and p-TrkBTyr816 were positively associated when SED and EX rats were simultaneously examined. The results incite to consider endothelial BDNF as a full and NO-dependent endothelium-derived factor that exerts autocrine effects.

Childhood Hypertension and Effects on Cognitive Functions: Mechanisms and Future Perspectives.

Pediatric hypertension is currently one of the most common health concerns in children, given its effects not only on cardiovascular but also cognitive functions. There is accumulating evidence suggesting neurocognitive dysfunction in hypertensive children that could persist even into adulthood. Identifying the precise mechanism(s) underlying the association between childhood hypertension and cognitive dysfunction is crucial as it could potentially lead to the discovery of "druggable" biological targets facilitating the development of treatments. Here, we discuss some of the proposed pathophysiological mechanisms underlying childhood hypertension and cognitive deficits and suggest strategies to address some of the current challenges in the field. The various research studies involving hypertensive adults indicate that long-term hypertension may produce abnormal cerebrovascular reactivity, chronic inflammation, autonomic dysfunction, or hyperinsulinemia and hypercholesterolemia, which could lead to alterations in the brain's structure and functions, resulting in cognitive dysfunction. In light of the current literature, we propose that dysregulation of the hypothalamus-pituitaryadrenal axis, modifications in endothelial brain-derived neurotrophic factor and the gut microbiome may also modulate cognitive functions in hypertensive individuals. Moreover, the above-mentioned pathological states may further intensify the detrimental effects of hypertension on cognitive functions. Thus, treatments that target not only hypertension but also its downstream effects may prove useful in ameliorating hypertension-induced cognitive deficits. Much remains to be clarified about the mechanisms and treatments of hypertension-induced cognitive outcomes in pediatric populations. Addressing the knowledge gaps in this field entails conducting not only clinical research but also rigorous basic and translational studies.

The Cerebral Brain-Derived Neurotrophic Factor Pathway, Either Neuronal or Endothelial, Is Impaired in Rats with Adjuvant-Induced Arthritis. Connection with Endothelial Dysfunction.

Cognitive abilities are largely dependent on activation of cerebral tropomyosin-related kinase B receptors (TrkB) by brain-derived neurotrophic factor (BDNF) that is secreted under a bioactive form by both neurons and endothelial cells. In addition, there is mounting evidence for a link between endothelial function and cognition even though the underlying mechanisms are not well known. Therefore, we investigated the cerebral BDNF pathway, either neuronal or endothelial, in rheumatoid arthritis (RA) that combines both endothelial dysfunction (ED) and impaired cognition. Adjuvant-induced arthritis (AIA) in rats was used as a model of RA. Clinical inflammatory symptoms were evaluated from an arthritis score and brains were collected at day 31 ± 2 post-immunization. Neuronal expression of BDNF and TrkB phosphorylated at tyrosine 816 (p-TrkB) was examined in brain slices. Endothelial BDNF and p-TrkB expression was examined on both brain slices (hippocampal arterioles) and isolated cerebral microvessels-enriched fractions (vessels downstream to arterioles). The connection between endothelial nitric oxide (NO) and BDNF production was explored on the cerebrovascular fractions using endothelial NO synthase (eNOS) levels as a marker of NO production, Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) as a NOS inhibitor and glyceryl-trinitrate as a slow releasing NO donor. Brain slices displayed lower BDNF and p-TrkB staining in both neurons and arteriolar endothelial cells in AIA than in control rats. For endothelial cells but not neurons, a strong correlation was observed between BDNF and p-TrkB staining. Of note, a strong correlation was also observed between neuronal p-TrkB and endothelial BDNF staining. In cerebral microvessels-enriched fractions, AIA led to decreased BDNF and eNOS levels with a positive association between the 2 parameters. These effects coincided with decreased BDNF and p-TrkB staining in endothelial cells. The exposure of AIA cerebrovascular fractions to GTN increased BDNF levels while the exposure of control fractions to L-NAME decreased BDNF levels. Changes in the cerebral BDNF pathway were not associated with arthritis score. The present study reveals that AIA impairs the endothelial and neuronal BDNF/TrkB pathway, irrespective of the severity of inflammatory symptoms but dependent on endothelial NO production. These results open new perspectives for the understanding of the link between ED and impaired cognition.

Physical training and hypertension have opposite effects on endothelial brain-derived neurotrophic factor expression

Changes in circulating brain-derived neurotrophic factor (BDNF) levels were reported in patients with or at risk for cardiovascular diseases associated with endothelial dysfunction, suggesting a link between BDNF and endothelial functionality. However, little is known on cardiovascular BDNF. Our aim was to investigate levels/localization, function, and relevance of cardiovascular BDNF. BDNF levels (western blotting) and localization (immunostaining) were assessed in the heart and aorta from rats with impaired (spontaneously hypertensive rats [SHR]), normal (Wistar Kyoto rats [WKY]), and improved (SHR and WKY subjected to physical training) endothelial function. BDNF levels were also measured in cultured endothelial cells (CECs) subjected to low and high shear stress. The cardiovascular effects of BDNF were investigated in isolated aortic rings and hearts. The results showed high BDNF levels in the heart and aorta, the expression being prominent in endothelial cells as compared with other cell types. Exogenous BDNF vasodilated aortic rings but changed neither coronary flow nor cardiac contractility. Hypertension was associated with decreased expression of BDNF in the endothelium, whereas physical training led to endothelial BDNF up-regulation not only in WKY but also in SHR. Exposure of CECs to high shear stress stimulated BDNF production and secretion. Cardiovascular BDNF is mainly localized within endothelial cells in which its expression is dependent on endothelial function. These results open new perspectives on the role of endothelial BDNF in cardiovascular health.