Sub-Chronic Stress Exacerbates the Pro-Thrombotic Phenotype in BDNFVal/Met Mice: Gene-Environment Interaction in the Modulation of Arterial Thrombosis

Abstract

Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been associated with increased susceptibility to develop mood disorders and recently it has been also linked with cardiovascular disease (CVD). Interestingly, stressful conditions unveil the anxious/depressive-like behavioral phenotype in heterozygous BDNFVal66Met (BDNFVal/Met) mice, suggesting an important relationship in terms of gene-environment interaction (GxE). However, the interplay between stress and BDNFVal/Met in relation to CVD is completely unknown. Here, we showed that BDNFVal/Met mice display a greater propensity to arterial thrombosis than wild type BDNFVal/Val mice after 7 days of restraint stress (RS). RS markedly increased the number of leukocytes and platelets, and induced hyper-responsive platelets as showed by increased circulating platelet/leukocyte aggregates and enhanced expression of P-selectin and GPIIbIIIa in heterozygous mutant mice. In addition, stressed BDNFVal/Met mice had a greater number of large and reticulated platelets but comparable number and maturation profile of bone marrow megakaryocytes compared to BDNFVal/Val mice. Interestingly, RS led to a significant reduction of BDNF expression accompanied by an increased activity of tissue factor in the aorta of both BDNFVal/Val and BDNFVal/Met mice. In conclusion, we provide evidence that sub-chronic stress unveils prothrombotic phenotype in heterozygous BDNF Val66Met mice affecting both the number and functionality of blood circulating cells, and the expression of key thrombotic molecules in aorta. Human studies will be crucial to understand whether this GxE interaction need to be taken into account in risk stratification of coronary artery disease (CAD) patients.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in a Community-Based Cohort: Data From the Washington, D.C. Cardiovascular Health and Needs Assessment

“…These findings are further supported by the evidence that brain centers can activate bone marrow cells to promote arterial hypertension in animal models ( 40 ). Moreover, recent work in mice demonstrates that induced chronic stress can lead to a prothrombotic state for those with a genetic predisposition to anxiety and depression, highlighting potential gene-by-environment interactions that lead psychosocial stressors to increase cardiovascular risk ( 41 ). Further translational work in humans should explore how immune cell function may influence vascular health in the setting of chronic social stressors.…”

Physical Exercise Affects Adipose Tissue Profile and Prevents Arterial Thrombosis in BDNF Val66Met Mice

“…Experimental arterial thrombosis was induced as previously described [39]. Briefly, the left carotid artery of anesthetized mice was freely dissected, and a flow probe (model 0.7 VB, Transonic System, Ithaca, NY, USA) connected to a transonic flowmeter (TransonicT106) was used to measure blood flow.…”

“…Samples of cDNA were incubated in 15 µL Luna ® Universal qPCR mix containing the specific primers and fluorescent dye SYBR Green (New England Biolabs, Pero, Milan, Italy). RT-qPCR was carried out in triplicate for each sample on the CFX Connect real-time System (Bio-Rad Laboratories, Segrate, Milan, Italy) as previously described [39]. Gene expression was analyzed using parameters available in CFX Manager Software 3.1 (Bio-Rad Laboratories, Segrate, Milan, Italy).…”

Depression and Cardiovascular Disease: The Viewpoint of Platelets

“…The genetic knock-in mouse carrying BDNFVal66Met polymorphisms, that recapitulates the phenotypic hallmarks of human disease (e.g., depression and CVD) [179] has been a helpful model to investigate the relationship between this polymorphism and platelet function. Specifically, the presence of this polymorphism predisposes to platelet hyper-activated phenotype, enhancing Pselectin expression, GPIIb/IIIa receptor activity, ability to bind leukocytes and fibrinogen, and aggregation [179,225]. The controversial role of BDNF on platelet function.…”