Diabetes is a major risk factor for tendinopathy, and tendon abnormalities are common in diabetic patients. The purpose of the present study was to evaluate the effect of streptozotocin (60 mg/kg)-induced diabetes and insulin therapy on tendon mechanical and cellular properties. Sprague-Dawley rats ( n = 40) were divided into the following four groups: nondiabetic (control), 1 wk of diabetes (acute), 10 wk of diabetes (chronic), and 10 wk of diabetes with insulin treatment (insulin). After 10 wk, Achilles tendon and tail fascicle mechanical properties were similar between groups ( P > 0.05). Cell density in the Achilles tendon was greater in the chronic group compared with the control and acute groups (control group: 7.8 ± 0.5 cells/100 μm², acute group: 8.3 ± 0.4 cells/100 μm², chronic group: 10.9 ± 0.9 cells/100 μm², and insulin group: 9.2 ± 0.8 cells/100 μm², P < 0.05). The density of proliferating cells in the Achilles tendon was greater in the chronic group compared with all other groups (control group: 0.025 ± 0.009 cells/100 μm², acute group: 0.019 ± 0.005 cells/100 μm², chronic group: 0.067 ± 0.015, and insulin group: 0.004 ± 0.004 cells/100 μm², P < 0.05). Patellar tendon collagen content was ∼32% greater in the chronic and acute groups compared with the control or insulin groups (control group: 681 ± 63 μg collagen/mg dry wt, acute group: 938 ± 21 μg collagen/mg dry wt, chronic: 951 ± 52 μg collagen/mg dry wt, and insulin group: 596 ± 84 μg collagen/mg dry wt, P < 0.05). In contrast, patellar tendon hydroxylysyl pyridinoline cross linking and collagen fibril organization were unchanged by diabetes or insulin ( P > 0.05). Our findings suggest that 10 wk of streptozotocin-induced diabetes does not alter rat tendon mechanical properties even with an increase in collagen content. Future studies could attempt to further address the mechanisms contributing to the increase in tendon problems noted in diabetic patients, especially since our data suggest that hyperglycemia per se does not alter tendon mechanical properties.

Transient ACE (angiotensin-converting enzyme) inhibition in spontaneously hypertensive rats is known to protect against future injury-induced cardiac inflammation, fibrosis, and dysfunction; however, the mechanisms of protection have not been delineated. Here, we used single-cell RNA sequencing to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in cardiac fibroblast subpopulations. Adult male spontaneously hypertensive rats (11 weeks old, hypertensive with cardiac hypertrophy) were treated for 2 weeks with an ACE inhibitor, enalapril (30 mg/kg per day, PO), or water (untreated spontaneously hypertensive rats) followed by a 2-week washout period (n=7/group). Cardiac fibroblasts were isolated from the left ventricle and subjected to single-cell RNA sequencing. Nine clusters of fibroblasts were identified, with 98% of cells in clusters 0 to 6. The transient treatment produced significant changes both within and across clusters. Cluster 1 depicted a highly fibrogenic gene profile, with cluster 6 serving as a gateway to cluster 1. Transient ACE inhibition depleted the gateway and expanded cluster 0, which was the least fibrogenic profile. Moreover, within cluster 1 fibroblasts, ACE inhibition reduced expression of individual fibrosis genes (eg, COL1A1, COL3A1 , and FN1 ; all P <1×10 ^-35 ). Clusters 2 to 5 reflected proliferative, moderately fibrogenic, translationally active, and less inflammatory subsets of fibroblasts, all of which exhibited attenuated fibrogenic gene expression after transient ACE inhibition. In conclusion, transient ACE inhibition shifts cardiac fibroblast subpopulations and degree of activation resulting in an overall reduced fibrogenic phenotype.

Androgens play a pivotal role during development. These gonadal hormones and their receptors exert organizational actions that shape brain morphology in regions controlling the stress regulatory systems in a male-specific manner. Specifically, androgens drive sex differences in the hypothalamic/pituitary/adrenal (HPA) axis and corresponding hypothalamic neuropeptides. While studies have examined the role of estradiol and its receptors in sex differences in the HPA axis and associated behaviors, the role of androgens remains far less studied. Androgens are generally thought to modulate the HPA axis through the activation of androgen receptors (ARs). They can also impact the HPA axis through reduction to estrogenic metabolites that can bind estrogen receptors in the brain and periphery. Such regulation of the HPA axis stress response by androgens can often result in sex-biased risk factors for stress-related disorders, such as anxiety and depression. This review focuses on the biosynthesis pathways and molecular actions of androgens and their nuclear receptors. The impact of androgens on hypothalamic neuropeptide systems (corticotropin-releasing hormone, arginine vasopressin, oxytocin, dopamine, and serotonin) that control the stress response and stress-related disorders is discussed. Finally, this review discusses potential therapeutics involving androgens (androgen replacement therapies, selective AR modulator therapies) and ongoing clinical trials.

Approximately 50% of Americans have hypertension, which significantly increases the risk of heart failure. In response to increased peripheral resistance in hypertension, intensified mechanical stretch in the myocardium induces cardiomyocyte hypertrophy and fibroblast activation to withstand increased pressure overload. This changes the structure and function of the heart, leading to pathological cardiac remodeling and eventual progression to heart failure. In the presence of hypertensive stimuli, cardiac fibroblasts activate and differentiate to myofibroblast phenotype capable of enhanced extracellular matrix secretion in coordination with other cell types, mainly cardiomyocytes. Both systemic and local renin-angiotensin-aldosterone system activation lead to increased angiotensin II stimulation of fibroblasts. Angiotensin II directly activates fibrotic signaling such as transforming growth factor β/SMAD and mitogen-activated protein kinase (MAPK) signaling to produce extracellular matrix comprised of collagens and matricellular proteins. With the advent of single-cell RNA sequencing techniques, heterogeneity in fibroblast populations has been identified in the left ventricle in models of hypertension and pressure overload. The various clusters of fibroblasts reveal a range of phenotypes and activation states. Select antihypertensive therapies have been shown to be effective in limiting fibrosis, with some having direct actions on cardiac fibroblasts. The present review focuses on the fibroblast-specific changes that occur in response to hypertension and pressure overload, the knowledge gained from single-cell analyses, and the effect of antihypertensive therapies. Understanding the dynamics of hypertensive fibroblast populations and their similarities and differences by sex is crucial for the advent of new targets and personalized medicine.