RESUMO
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 ß/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.
Assuntos
Insuficiência Cardíaca , Hipertensão , Humanos , Anti-Hipertensivos/farmacologia , Angiotensina II/farmacologia , Miocárdio/metabolismo , Hipertensão/metabolismo , Fibroblastos/metabolismo , FibroseRESUMO
Assessment of hypertensive tubulopathy for more than fifty animal models of hypertension in experimental pathology employs criteria that do not correspond to lesional descriptors for tubular lesions in clinical pathology. We provide a critical appraisal of experimental hypertension with the same approach used to estimate hypertensive renal tubulopathy in humans. Four models with different pathogenesis of hypertension were analyzed-chronic angiotensin (Ang) II-infused and renin-overexpressing (TTRhRen) mice, spontaneously hypertensive (SHR), and Goldblatt two-kidney one-clip (2K1C) rats. Mouse models, SHR, and the nonclipped kidney in 2K1C rats had no regular signs of hypertensive tubulopathy. Histopathology in animals was mild and limited to variations in the volume density of tubular lumen and epithelium, interstitial space, and interstitial collagen. Affected kidneys in animals demonstrated lesion values that are significantly different compared with healthy controls but correspond to mild damage if compared with hypertensive humans. The most substantial human-like hypertensive tubulopathy was detected in the clipped kidney of 2K1C rats. For the first time, our study demonstrated the regular presence of chronic progressive nephropathy (CPN) in relatively young mice and rats with induced hypertension. Because CPN may confound the assessment of rodent models of hypertension, proliferative markers should be used to verify nonhypertensive tubulopathy.
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Hipertensão , Patologia Clínica , Humanos , Ratos , Camundongos , Animais , Ratos Endogâmicos SHR , Rim , Modelos Animais de DoençasAssuntos
Envelhecimento , Coração , Animais , Feminino , Fibrose , Masculino , Camundongos , FenótipoRESUMO
The purpose of this study was to evaluate the role of TGF-ß1 in regulating tendon extracellular matrix after acute exercise. Wistar rats exercised (n = 15) on a treadmill for four consecutive days (60 min/day) or maintained normal cage activity. After each exercise bout, the peritendinous space of each Achilles tendon was injected with a TGF-ß1 receptor inhibitor or sham. Independent of group, tendons injected with inhibitor exhibited ~50% lower Smad 3 (Ser423/425) (P < 0.05) and 2.5-fold greater ERK1/2 phosphorylation (P < 0.05) when compared with sham (P < 0.05). Injection of the inhibitor did not alter collagen content in either group (P > 0.05). In exercised rats, hydroxylyslpyridinoline content and collagen III expression were lower (P < 0.05) in tendons injected with inhibitor when compared with sham. In nonexercised rats, collagen I and lysyl oxidase (LOX) expression was lower (P < 0.05) in tendons injected with inhibitor when compared with sham. Decorin expression was not altered by inhibitor in either group (P > 0.05). On the basis of evaluation of hematoxylin and eosin (H&E) stained cross sections, cell numbers were not altered by inhibitor treatment in either group (P > 0.05). Evaluation of H&E-stained sections revealed no effect of inhibitor on collagen fibril morphology. In contrast, scores for regional variation in cellularity decreased in exercised rats (P < 0.05). No differences in fiber arrangement, structure, and nuclei form were noted in either group (P > 0.05). Our findings suggest that TGF-ß1 signaling is necessary for the regulation of tendon cross-link formation, as well as collagen and LOX gene transcription in an exercise-dependent manner.
Assuntos
Tendão do Calcâneo/fisiologia , Colágeno Tipo I/metabolismo , Matriz Extracelular/fisiologia , Condicionamento Físico Animal/métodos , Proteína-Lisina 6-Oxidase/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Proteínas da Matriz Extracelular/metabolismo , Masculino , Esforço Físico/fisiologia , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta1/antagonistas & inibidoresRESUMO
Fibrotic cardiac remodeling ultimately leads to heart failure - a debilitating and costly condition. Select antihypertensive agents have been effective in reducing or slowing the development of cardiac fibrosis. Moreover, some experimental studies have shown that the reduction in fibrosis induced by these agents persists long after stopping treatment. What has not been as well investigated is whether this transient treatment results in a protection against future fibrotic cardiac remodeling. In the present review, previously published studies are re-examined to assess whether the relative percent increase in collagen deposition over an off-treatment period is attenuated, relative to control, following transient antihypertensive treatment in young or adult rats. Present findings suggest that transient inhibition of the renin angiotensin system (RAS) not only produces a sustained reduction in cardiac fibrosis, but also results in a degree of protection against future collagen deposition. In addition, prior transient RAS inhibition appears to alter the cardiac fibroblast phenotype such that these cells show a muted response to myocardial injury - namely reduced proliferation, chemokine release, and collagen deposition. This review puts forth several potential mechanisms underlying this long-term cardiac protection that is afforded by transient RAS inhibition. Specifically, fibroblast phenotypic change, cardiac fibroblast apoptosis, sustained suppression of the RAS, persistent reduction in left ventricular hypertrophy, and persistent reduction in arterial pressure are each discussed. Identifying the mechanisms ultimately responsible for this change in cardiac fibroblast response to injury, hypertension, and aging may reveal novel targets for therapy.
Assuntos
Transdiferenciação Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fenótipo , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Apoptose , Fibrose , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Sistema Renina-Angiotensina/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
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 µm(2), acute group: 8.3 ± 0.4 cells/100 µm(2), chronic group: 10.9 ± 0.9 cells/100 µm(2), and insulin group: 9.2 ± 0.8 cells/100 µm(2), 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 µm(2), acute group: 0.019 ± 0.005 cells/100 µm(2), chronic group: 0.067 ± 0.015, and insulin group: 0.004 ± 0.004 cells/100 µm(2), P < 0.05). Patellar tendon collagen content was â¼32% 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.
Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Tendões/patologia , Tendões/fisiopatologia , Doença Aguda , Animais , Doença Crônica , Colágeno/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Módulo de Elasticidade , Matriz Extracelular/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina , Estresse Mecânico , Resistência à TraçãoRESUMO
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.
Assuntos
Angiotensina II/toxicidade , Modelos Animais de Doenças , Glomerulosclerose Segmentar e Focal/patologia , Hipertensão Renal/patologia , Hipertensão/complicações , Nefrite/patologia , Nefroesclerose/patologia , Animais , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/metabolismo , Humanos , Hipertensão/induzido quimicamente , Hipertensão Renal/etiologia , Hipertensão Renal/metabolismo , Masculino , Nefrite/etiologia , Nefrite/metabolismo , Nefroesclerose/etiologia , Nefroesclerose/metabolismo , Ratos , Ratos Endogâmicos SHR , Vasoconstritores/toxicidadeRESUMO
Cardiac fibrosis is characteristic of the end stage in nearly all forms of heart disease. Accumulation of extracellular matrix in the myocardium leads to increased risk of arrhythmia and impaired cardiac function, and ultimately progression to heart failure. Despite the critical need to slow or reverse development of cardiac fibrosis to maintain cardiac function, there are no approved therapies that directly target the extracellular matrix. Research into the underlying causes and therapeutic targets has been hampered, in part, by the lack of a clear marker for cardiac fibroblasts - the cells responsible for regulating extracellular matrix turnover. Lineage tracing studies as well as single-cell RNA sequencing studies have provided new insights into cardiac fibroblast origins and heterogeneity. Moreover, a greater understanding of pathways governing fibroblast activation during ischemic and non-ischemic cardiac remodeling and their communication with other inflammatory and cardiac cells may lead to novel therapeutic targets to slow or reverse fibrotic remodeling. The special issue of Cellular Signaling entitled "Cardiac Fibrosis: Pathobiology and Therapeutic Targets" is comprised of review articles in which these topics, as well as important open questions for future investigation, are discussed.
Assuntos
Fibroblastos , Miocárdio , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrose , Coração , Humanos , Miocárdio/metabolismoRESUMO
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.
RESUMO
Angiotensin II (Ang II) is a primary mediator of profibrotic signaling in the heart and more specifically, the cardiac fibroblast. Ang II-mediated cardiomyocyte hypertrophy in combination with cardiac fibroblast proliferation, activation, and extracellular matrix production compromise cardiac function and increase mortality in humans. Profibrotic actions of Ang II are mediated by increasing production of fibrogenic mediators (e.g. transforming growth factor beta, scleraxis, osteopontin, and periostin), recruitment of immune cells, and via increased reactive oxygen species generation. Drugs that inhibit Ang II production or action, collectively referred to as renin angiotensin system (RAS) inhibitors, are first line therapeutics for heart failure. Moreover, transient RAS inhibition has been found to persistently alter hypertensive cardiac fibroblast responses to injury providing a useful tool to identify novel therapeutic targets. This review summarizes the profibrotic actions of Ang II and the known impact of RAS inhibition on cardiac fibroblast phenotype and cardiac remodeling.
Assuntos
Fibroblastos/metabolismo , Sistema Renina-Angiotensina , Angiotensina II/genética , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Epigênese Genética , Fibroblastos/citologia , Fibrose , Humanos , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
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.
Assuntos
Enalapril/farmacologia , Fibroblastos/efeitos dos fármacos , Coração/efeitos dos fármacos , Hipertensão/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Células Cultivadas , Análise por Conglomerados , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Colágeno Tipo III/genética , Fibroblastos/metabolismo , Fibronectinas/genética , Fibrose , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/fisiopatologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Endogâmicos SHRRESUMO
Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor ß (TGFß) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFß signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.
Assuntos
Proteínas da Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibrose/prevenção & controle , Terapia de Alvo Molecular/métodos , Sistema Renina-Angiotensina/efeitos dos fármacos , Amidas/uso terapêutico , Angiotensinas/antagonistas & inibidores , Angiotensinas/genética , Angiotensinas/metabolismo , Animais , Benzimidazóis/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Matriz Extracelular/química , Proteínas da Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Fumaratos/uso terapêutico , Regulação da Expressão Gênica , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Piridonas/uso terapêutico , Sistema Renina-Angiotensina/genética , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Tetrazóis/uso terapêutico , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
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.
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Tendinopathy risk increases with menopause. The phytoestrogen genistein prevents collagen loss during estrogen deficiency (ovariectomy [OVX]). The influence of genistein on tendon function and extracellular matrix (ECM) regulation is not well known. We determined the impact of genistein on tendon function and the expression of several genes important for the regulation of tendon ECM. Eight-week-old rats (n = 42) were divided into three groups: intact, OVX, or OVX-genistein (6 mg/kg/day) for 6 weeks. Tail fascicles were assessed with a Deben tensile stage. Achilles tendon mRNA expression was determined with digital droplet polymerase chain reaction. Compared to intact, fascicle stress tended to be lower in untreated OVX rats (P = .022). Furthermore, fascicle modulus and energy density were greater in genistein-treated rats (P < .05) compared to intact. Neither OVX nor genistein altered expression of Col1a1, Col3a1, Casp3, Casp8, Mmp1a, Mmp2, or Mmp9 (P > .05). Compared to intact, Tnmd and Esr1 expression were greater and Pcna and Timp1 expression were lower in OVX rats (P < .05). Genistein treatment returned Tnmd, Pcna, and Timp1 to levels of intact-vehicle (P < .05), but did not alter Scx or Esr1 (P > .05). Several ß-catenin/Wnt signaling-related molecules were not altered by OVX or genistein (P > .05). Our findings demonstrate that genistein improves tendon function in estrogen-deficient rats. The effect of genistein in vivo was predominately on genes related to cell proliferation rather than collagen remodeling.
Assuntos
Suplementos Nutricionais , Genisteína/farmacologia , Tendões/efeitos dos fármacos , Tendões/fisiologia , Animais , Feminino , Expressão Gênica , Ovariectomia , RatosRESUMO
INTRODUCTION: Erectile dysfunction (ED) and cardiovascular disease often coexist and have many common risk factors. In hypertension, the structure of blood vessels is modified such that there is an increase in medial wall thickness relative to lumen size. Certain antihypertensive agents have been found to induce a regression of vascular structure such that a "hypertensive" vessel appears phenotypically more like that from a normotensive. AIM: To provide an update on the findings to date on the impact of vascular remodeling on erectile function. MAIN OUTCOME MEASURES: Review of peer reviewed literature related to vascular remodeling induced by antihypertensive agents and the potential impact on sexual function. METHODS: A literature review was performed on clinical and experimental evidence regarding the association between cardiovascular disease and ED, the impact of vascular remodeling on these conditions, the impact of antihypertensive therapy on ED, and the mechanisms of antihypertensive drug-induced remodeling. RESULTS: There is increasing evidence that ED may be an early marker for progressing cardiovascular disease. Certain antihypertensive agents have beneficial effects on both vascular structure and erectile function. The major site of resistance in the penile vasculature occurs at the level of the pudendal artery. Although structural remodeling has not yet been investigated in this vessel specifically, antihypertensive drugs have been shown to induce remodeling of the pudendal-penile vasculature and cavernosal arteries. Antihypertensive drug-induced vascular remodeling can be characterized by a decrease in the ratio of wall thickness to lumen diameter, and may result from vascular smooth muscle cell apoptosis, rearrangement of cells around a smaller lumen, and/or changes in the extracellular matrix composition depending on the vessel type. CONCLUSION: Determining the mechanisms involved in antihypertensive drug-induced vascular remodeling in the pudendal vasculature may provide novel targets for the treatment of ED.
Assuntos
Anti-Hipertensivos/efeitos adversos , Disfunção Erétil/epidemiologia , Disfunção Erétil/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Pênis/irrigação sanguínea , Anti-Hipertensivos/uso terapêutico , Apoptose/fisiologia , Artérias/fisiologia , Disfunção Erétil/induzido quimicamente , Humanos , Hipotálamo/fisiologia , Masculino , Músculo Liso/irrigação sanguínea , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Músculo Liso/fisiopatologia , Vias Neurais , Transdução de Sinais , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia , Resistência Vascular/fisiologia , Vasodilatação/fisiologiaRESUMO
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 mgâkg-1 ; cumulative dose 12 mgâkg-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.
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Antibióticos Antineoplásicos/administração & dosagem , Capilares/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Animais , Feminino , Músculo Esquelético/irrigação sanguínea , Ratos , Ratos Sprague-DawleyRESUMO
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.