An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms.

Angiotensin, which regulates blood pressure may also act within the brain to mediate stress and fear responses. Common antihypertensive medication classes of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) have been associated with lower PTSD symptoms. Here we examine the rs4311 SNP in the ACE gene, previously implicated in panic attacks, in the relationship between ACE-I/ARB medications and PTSD symptoms. Participants were recruited from outpatient wait rooms between 2006 and March 2014 (n= 803). We examined the interaction between rs4311 genotype and the presence of blood pressure medication on PTSD symptoms and diagnosis. PTSD symptoms were lower in individuals taking ACE-Is or ARBs (N = 776). The rs4311 was associated with PTSD symptoms and diagnosis (N = 3803), as the T-carriers at the rs4311 SNP had significantly greater likelihood of a PTSD diagnosis. Lastly, the rs4311 genotype modified the effect of ACE-Is or ARBs on PTSD symptoms (N = 443; F1,443 = 4.41, P < 0.05). Individuals with the CC rs4311 genotype showed lower PTSD symptoms in the presence of ACE-Is or ARBs. In contrast, T- carriers showed the opposite, such that the presence of ACE-Is or ARBs was associated with higher PTSD symptoms. These data suggest that the renin-angiotensin system may be important in PTSD, as ACE-I/ARB usage associates with lower symptoms. Furthermore, we provide genetic evidence that some individuals are comparatively more benefitted by ACE-Is/ARBs in PTSD treatment. Future research should examine the mechanisms by which ACE-Is/ARBs affect PTSD symptoms such that pharmaco-genetically informed interventions may be used to treat PTSD.

Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear.

Although generally associated with cardiovascular regulation, angiotensin II receptor type 1a (AT1a R) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post-traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin-releasing factor (CRF)-expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT1a R signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT1a R gene from its CRF-releasing cells (CRF-AT1a R((-/-)) ). These mice exhibit normal baseline heart rate, blood pressure, anxiety and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF-AT1a R((-/-)) mice exhibit less freezing than wild-type mice during tests of conditioned fear expression-an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT1a R activity in CRF-expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT1 R antagonists may act to modulate fear extinction.

Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction.

Perivascular adipose tissue AT is a critical regulator of vascular function, which until recently has been greatly overlooked. Virtually all arteries are surrounded by a significant amount of perivascular adipose tissue, which has long been considered to serve primarily a supportive, mechanical purpose. Recent studies show that both visceral and perivascular fat is a very active endocrine and paracrine source of inflammatory cytokines and adipokines. The latter include beneficial adipocytokines such as adiponectin or so far unidentified adipocyte derived relaxing factor (ADRF) as the presence of perivascular AT may decrease contractile responses to vasoconstrictive agents. However, in pathological states such as obesity, hypertension, diabetes metabolic syndrome and other cardiovascular disorders perivascular tissue becomes dysfunctional and production of protective factors diminishes while detrimental adipocytokines such as leptin, resistin, IL-6, TNF-alpha or IL-17 increases. Moreover the dysfunction of perivascular fat can lead to imbalance between vascular nitric oxide (NO) and superoxide production. Adipokines also regulate immune system as chemokines (such as MIP-1 or RANTES) and induce inflammation with infiltration of T cells and macrophages to the vessel wall. Interestingly central nervous system can affect vascular function through mediation of perivascular adipose tissue dysfunction. In particular sympathetic nervous system endings are present in both visceral and perivascular AT. This powerful relationship between the brain and the vessel can be termed "brain-vessel axis" in which--we propose in the Review--perivascular adipose tissue may take center stage. The role of perivascular fat in the regulation of blood vessels depends on metabolic state, inflammation and clinical risk factors. In health protective and vasorelaxant properties of perivascular AT dominate while in pathology pathogenetic influences including neural stimulation of sympathetic nerve endings or humoral effects of certain hormones and adipocytokines dominates. We propose to term this state "perivascular adipose tissue dysfunction" in similarity to endothelial dysfunction.