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

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 (BDNF(Val/Met)) mice, suggesting an important relationship in terms of gene-environment interaction (GxE). However, the interplay between stress and BDNF(Val/Met) in relation to CVD is completely unknown. Here, we showed that BDNF(Val/Met) mice display a greater propensity to arterial thrombosis than wild type BDNF(Val/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 BDNF(Val/Met) mice had a greater number of large and reticulated platelets but comparable number and maturation profile of bone marrow megakaryocytes compared to BDNF(Val/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 BDNF(Val/Val) and BDNF(Val/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.