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The hypothalamic-pituitary-adrenal axis is a complex system of neuroendocrine pathways and feedback loops that function to maintain physiological homeostasis. Abnormal development of the hypothalamic-pituitary-adrenal (HPA) axis can further result in long-term alterations in neuropeptide and neurotransmitter synthesis in the central nervous system, as well as glucocorticoid hormone synthesis in the periphery. Together, these changes can potentially lead to a disruption in neuroendocrine, behavioral, autonomic, and metabolic functions in adulthood. In this review, we will discuss the regulation of the HPA axis and its development. We will also examine the maternal-fetal hypothalamic-pituitary-adrenal axis and disruption of the normal fetal environment which becomes a major risk factor for many neurodevelopmental pathologies in adulthood, such as major depressive disorder, anxiety, schizophrenia, and others.

Overall, they report that despite treatment-related impacts on fetal cardiac growth rates, cardiac function was largely unchanged until 12 months of age, when female offspring of dams exposed to ethanol exhibited a significant reduction in cardiac output. Identifying the pathophysiology underlying the female-specific reduction in cardiac output will be important not only for determining the in utero drivers of future cardiac dysfunction attributable to periconceptional ethanol exposure, but also for developing future treatment strategies. [...]given the impaired cardiac function in the female offspring, it will be important to evaluate the degree to which these animals are more susceptible to developing heart failure. Specifically, future studies that are designed to evaluate the degree to which periconceptional ethanol exposure confers an increased risk for cardiac dysfunction and pathological remodelling after myocardial infarction or pressure overload would be of significant interest and would provide greater insight into the cardiovascular risk profile in response to early ethanol exposure.

Current research on hypertension utilizes more than fifty animal models that rely mainly on stable increases in systolic blood pressure. In experimental hypertension, grading or scoring of glomerulopathy in the majority of studies is based on a wide range of opinion-based histological changes that do not necessarily comply with lesional descriptors for glomerular injury that are well-established in clinical pathology. Here, we provide a critical appraisal of experimental hypertensive glomerulopathy with the same approach used to assess hypertensive glomerulopathy in humans. Four hypertensive models with varying pathogenesis were analyzed–chronic angiotensin II infused mice, mice expressing active human renin in the liver (TTRhRen), spontaneously hypertensive rats (SHR), and Goldblatt two-kidney one-clip rats (2K1C). Analysis of glomerulopathy utilized the same criteria applied in humans–hyalinosis, focal segmental glomerulosclerosis (FSGS), ischemic, hypertrophic and solidified glomeruli, or global glomerulosclerosis (GGS). Data from animal models were compared to human reference values. Kidneys in TTRhRen mice, SHR and the nonclipped kidneys in 2K1C rats had no sign of hyalinosis, FSGS or GGS. Glomerulopathy in these groups was limited to variations in mesangial and capillary compartment volumes, with mild increases in collagen deposition. Histopathology in angiotensin II infused mice corresponded to mesangioproliferative glomerulonephritis, but not hypertensive glomerulosclerosis. The number of nephrons was significantly reduced in TTRhRen mice and SHR, but did not correlate with severity of glomerulopathy. The most substantial human-like glomerulosclerotic lesions, including FSGS, ischemic obsolescent glomeruli and GGS, were found in the clipped kidneys of 2K1C rats. The comparison of affected kidneys to healthy control in animals produces lesion values that are numerically impressive but correspond to mild damage if compared to humans. Animal studies should be standardized by employing the criteria and classifications established in human pathology to make experimental and human data fully comparable for comprehensive analysis and model improvements.

We have previously demonstrated that angiotensin-converting enzyme (ACE) inhibition with enalapril produces persistent effects that protect against future nitric oxide synthase (NOS) inhibitor (L-arginine methyl ester, L-NAME)-induced cardiac dysfunction and outer wall collagen deposition in spontaneously hypertensive rats (SHR). In the present study, we dissect the cytokine/chemokine release profile during NOS inhibition, its correlation to pathological cardiac remodeling and the impact of transient ACE inhibition on these effects. Adult male SHR were treated with enalapril (E+L) or tap water (C+L) for 2 weeks followed by a 2-week washout period. Rats were then subjected to 0, 3, 7 or 10 days of L-NAME treatment. The temporal response to NOS inhibition was evaluated by measuring arterial pressure, cardiac remodeling and cytokine/chemokine levels. L-NAME equivalently increased blood pressure and myocardial and vascular injury in C+L and E+L rats. However, pulse pressure (PP) was only transiently altered in C+L rats. The levels of several inflammatory mediators were increased during L-NAME treatment. However, interleukin-6 (IL-6) and IL-10 and monocyte chemoattractant protein-1 were uniquely increased in C+L hearts; whereas IL-4 and fractalkine were only elevated in E+L hearts. By days 7 and 10 of L-NAME treatment, there was a significant increase in the cardiac density of macrophages and proliferating cells, respectively only in C+L rats. Although myocardial injury was similar in both treatment groups, PP was not changed and there was a distinct cardiac chemokine/cytokine signature in rats previously treated with enalapril that may be related to the lack of proliferative response and macrophage infiltration in these hearts.

Anthracycline chemotherapies are effective at reducing disease recurrence and mortality in cancer patients. However, these drugs also contribute to skeletal muscle wasting and dysfunction. The purpose of this study was to assess the impact of chronic doxorubicin (DOX) administration on satellite cell and capillary densities in different skeletal muscles. We hypothesized that DOX would reduce satellite cell and capillary densities of the soleus (SOL) and extensor digitorum longus (EDL) muscles, along with muscle fiber size. Ovariectomized female Sprague‐Dawley rats were randomized to receive three bi‐weekly intraperitoneal injections of DOX (4 mg∙kg−1; cumulative dose 12 mg∙kg−1) or vehicle (VEH; saline). Animals were euthanized 5d following the last injection and the SOL and EDL were dissected and prepared for immunohistochemical and RT‐qPCR analyses. Relative to VEH, CSA of the SOL and EDL fibers were 26% and 33% smaller, respectively, in DOX (P < 0.05). In the SOL, satellite cell and capillary densities were 39% and 35% lower, respectively, in DOX (P < 0.05), whereas in the EDL satellite cell and capillary densities were unaffected by DOX administration (P > 0.05). Proliferating satellite cells were unaffected by DOX in the SOL (P > 0.05). In the SOL, MYF5 mRNA expression was increased in DOX (P < 0.05), while in the EDL MGF mRNA expression was reduced in DOX (P < 0.05). Chronic DOX administration is associated with reduced fiber size in the SOL and EDL; however, DOX appeared to reduce satellite cell and capillary densities only in the SOL. These findings highlight that therapeutic targets to protect skeletal muscle from DOX may vary across muscles. This paper demonstrates that chronic administration of the chemotherapeutic agent doxorubicin is associated with reduced fiber size in the soleus and extensor digitorum longus muscles of rats. However doxorubicin appears to reduce satellite cell and capillary densities only in the soleus. These findings highlight that therapeutic targets to protect skeletal muscle from doxorubicin may vary across muscles.

Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1‐Ren2 xenobiotic‐inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15‐month‐old transgenic rats were fed 0.15% indole‐3‐carbinol (I3C) chow to slowly induce renin‐dependent hypertension over a 6‐week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C‐treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus‐dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular‐renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health. In this manuscript we demonstrate that an increase in blood pressure ‐ driven by a genetic upregulation of the renin‐angiotensin system ‐ in a fashion that closely mimics the timing and rate of onset of hypertension in the human alters spatial memory performance in the rat.

Major depressive disorder topped ischemic heart disease as the number one cause of disability worldwide in 2012, and women have twice the risk of men. Further, the comorbidity of depression and cardiometabolic disorders will be one of the primary causes of disability worldwide by 2020, with women at twice the risk. Thus, understanding the sex-dependent comorbidities has public health consequences worldwide. We propose here that sex differences in MDD-cardiometabolic comorbidity originate, in part, from pathogenic processes initiated in fetal development that involve sex differences in shared pathophysiology between the brain, the vascular system, the CNS control of the heart and associated hormonal, immune, and metabolic physiology. Pathways implicate neurotrophic and angiogenic growth factors, gonadal hormone receptors, and neurotransmitters such as gamma amino butyric acid (GABA) on neuronal and vascular development of HPA axis regions, such as the paraventricular nucleus (PVN), in addition to blood pressure, in part through the renin–angiotensin system, and insulin and glucose metabolism. We show that the same prenatal exposures have consequences for sex differences across multiple organ systems that, in part, share common pathophysiology. Thus, we believe that applying a sex differences lens to understanding shared biologic substrates underlying these comorbidities will provide novel insights into the development of sex-dependent therapeutics. Further, taking a lifespan perspective beginning in fetal development provides the opportunity to target abnormalities early in the natural history of these disorders in a sex-dependent way.

To the Editor: The article by Richter et al. (Nov. 26 issue) 1 highlights the persistence of gender inequity and confirms the lack of advancement of women in academic medical leadership. 2,3 Equity in health leadership is both a fundamental social justice issue and a population health issue. 4,5 We propose that the time has come to move beyond describing the problems. It is time for effective large-scale change to move the dial on this issue. Building the evidence base on best practices to support gender equity is vital in order to achieve effective, long-term, sustainable career advancement for women in health, including . . .

It has been previously shown that long-term RAS inhibition induces regression of vascular structure and a reduction in MAP, both of which persist long after treatment is stopped. While the mechanism for these changes has not been fully elucidated, both apoptosis and rearrangement of VSMCs has been implicated in the resulting decrease in media and increase in lumen diameter. The present study examines the impact of short-term RAS inhibition on MAP, structurally-based vascular resistance and susceptibility to apoptosis during and/or after withdrawal of treatment. SHR were treated with enalapril or losartan (E, L=30 mg/kg per day, p.o, 7 or 14 days). MAP was continuously monitored via radiotelemetry. Structurally-based vascular resistance was assessed by hindlimb perfusion (Dextran-Tyrodes) at the end of treatment or 2wks after drug withdrawal. The hindlimb vascular properties assessed included: resistance at max dil (MD=lumen size) and at max con (MC=medial bulk). After 7 days of treatment, aortic and mesenteric vessels were excised, cleaned then incubated in Tyrodes (37°C, 1% O2, 6hrs). DNA was extracted (phenol : chloroform) and apoptosis was detected via DNA fragmentation. E and L induced similar reduction in off-treatment level of MAP (E: -12±2.3%, L: -12±5.0%). Further, a similar regression of medial bulk was induced following 7 (MC: E: -12±5.9%, L: -12±6.6%) and 14 (MC: E: -12±2.7%, L: -12±6.1%) days of treatment, with no impact on lumen. In contrast, 2wks after stopping enalapril treatment both indices of vascular structure were similarly changed: medial index (MC: -12±8.0%) and lumen (MD: -15±7.9%). DNA fragmentation response in aortic and mesenteric vessels revealed that 7 days of E or L treatment did not change the susceptibility to hypoxia-induced apoptosis. A major finding of the present study is that only 2 wks of RAS inhibition is required to induce persistent changes in MAP and structurally-based vascular resistance. In addition, given the discordance between changes in vascular media and lumen during the on and off-treatment period, the vascular structural remodeling appears to continue even in the absence of drug therapy. We have previously shown that hypoxia is an effective stimulus to determine susceptibility to cell death. The present findings demonstrate that although short-term RAS inhibition induces some vascular remodeling, this action is not associated with significant changes in the susceptibility of VSMC to induced apoptosis. These findings may suggest a lesser role for apoptosis in the mechanism of persistent changes in vascular structure than has been previously hypothesized.