RESUMEN
The 5-hydroxytryptamine 7 receptor (5-HT7) is necessary for 5-HT to cause a concentration-dependent vascular relaxation and hypotension. 5-HT7 is recognized as having biased signaling, transduced through either Gs or ß -arrestin. It is unknown whether 5-HT7 signals in a biased manner to cause vasorelaxation/hypotension. We used the recently described ß-arrestin selective 5-HT7 receptor agonist serodolin to test the hypothesis that 5-HT7 activation does not cause vascular relaxation or hypotension via the ß -arrestin pathway. Isolated abdominal aorta (no functional 5-HT7) and vena cava (functional 5-HT7) from male Sprague Dawley rats were used in isometric contractility studies. Serodolin (1 nM - 10 µM) did not change baseline tone of isolated tissues and did not relax the endothelin-1 (ET-1)-contracted vena cava or aorta. In the aorta, serodolin acted as a 5-HT2A receptor antagonist, evidenced by a rightward shift in 5-HT-induced concentration response curve [pEC50 5-HT [M]: Veh = 5.2 +/- 0.15; Ser (100 nM) = 4.49 +/- 0.08; p < 0.05]. In the vena cava, serodolin acted as a 5-HT7 receptor antagonist, shifting the concentration response curve to 5-HT left and upward (%10 µM NE contraction; Veh = 3.2 +/- 1.7; Ser (10 nM) = 58 +/- 11; p < 0.05) and blocking relaxation of pre-contracted tissue to the 5-HT1A/7 agonist 5-carboxamidotryptamine. In anesthetized rats, 5-HT or serodolin was infused at 5, 25 and 75 µg/kg/min, iv. Though 5-HT caused concentration-dependent depressor responses, serodolin caused an insignificant small depressor responses at all three infusion rates. With the final dose of serodolin on board, 5-HT was unable to reduce blood pressure. Collectively the data indicate that serodolin functions as a 5-HT7 antagonist with additional 5-HT2A blocking properties. 5-HT7 activation does not cause vascular relaxation or hypotension via the ß -arrestin pathway.
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Hipotensión , Serotonina , Ratas , Animales , Masculino , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , beta-Arrestinas , Ratas Sprague-DawleyRESUMEN
The adipokine chemerin may support blood pressure, evidenced by a fall in mean arterial pressure after whole body antisense oligonucleotide (ASO)-mediated knockdown of chemerin protein in rat models of normal and elevated blood pressure. Although the liver is the greatest contributor of circulating chemerin, liver-specific ASOs that abolished hepatic-derived chemerin did not change blood pressure. Thus, other sites must produce the chemerin that supports blood pressure. We hypothesize that the vasculature is a source of chemerin independent of the liver that supports arterial tone. RNAScope, PCR, Western blot analyses, ASOs, isometric contractility, and radiotelemetry were used in the Dahl salt-sensitive (SS) rat (male and female) on a normal diet. Retinoic acid receptor responder 2 (Rarres2) mRNA was detected in the smooth muscle, adventitia, and perivascular adipose tissue of the thoracic aorta. Chemerin protein was detected immunohistochemically in the endothelium, smooth muscle cells, adventitia, and perivascular adipose tissue. Chemerin colocalized with the vascular smooth muscle marker α-actin and the adipocyte marker perilipin. Importantly, chemerin protein in the thoracic aorta was not reduced when liver-derived chemerin was abolished by a liver-specific ASO against chemerin. Chemerin protein was similarly absent in arteries from a newly created global chemerin knockout in Dahl SS rats. Inhibition of the receptor Chemerin1 by the receptor antagonist CCX832 resulted in the loss of vascular tone that supports potential contributions of chemerin by both perivascular adipose tissue and the media. These data suggest that vessel-derived chemerin may support vascular tone locally through constitutive activation of Chemerin1. This posits chemerin as a potential therapeutic target in blood pressure regulation.NEW & NOTEWORTHY Vascular tunicas synthesizing chemerin is a new finding. Vascular chemerin is independent of hepatic-derived chemerin. Vasculature from both males and females have resident chemerin. Chemerin1 receptor activity supports vascular tone.
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Vasos Sanguíneos , Quimiocinas , Animales , Ratas , Técnicas de Silenciamiento del Gen , Hígado/metabolismo , Aorta/metabolismo , Quimiocinas/análisis , Quimiocinas/metabolismo , Músculo Liso Vascular/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologíaRESUMEN
A recognized vasodilator, the infusion of 5-hydroxytryptamine (5-HT, serotonin) decreases blood pressure through the reduction of total peripheral resistance in the rat. It is not clear which vascular beds/tissues are responsible for this fall. We hypothesized that an increase in blood flow within the skin, measured as an elevated temperature (T) in the thermoregulatory tail and paws, enables at least part of 5-HT-induced reduction in blood pressure through active vasodilation. The temperature of thermoregulatory regions of the skin of an anesthetized male, Sprague Dawley rats were measured using a Optris PI640 thermal camera. The blood pressure of the animal and the temperature of each paw and four locations along the tail (TL1-4) were recorded before, during, and after the infusion of 5-HT at a rate of 25 mg/min into a femoral vein. Contrary to our hypothesis, the temperature of the paws and tail was stable before and during 5-HT infusion and actually increased during the 15-min recovery period. This finding suggests that hyperemia of the skin circulation is not necessary for the fall in blood pressure observed with infused 5-HT, but that a reduction in cutaneous vascular resistance plays a part in the fall in total peripheral resistance.
RESUMEN
The adipokine chemerin is a candidate for connecting obesity to hypertension. Study objective: To test the hypothesis that a high fat (HF) diet stimulates dependence on chemerin for blood pressure regulation. Design: Blood pressure in male Sprague Dawley rats fed a control (10 % fat) or HF (60 % fat) diet from weaning was measured using radiotelemetry. Antisense oligonucleotides (ASOs), administered after 17 weeks of feeding, were used to abolish chemerin production. Results: The HF diet did not increase blood pressure (mm Hg; control = 117.0 ± 2.5; HF = 122.0 ± 2.2). An ASO against chemerin (dosed 1×/week, 4 weeks) similarly reduced blood pressure in the control (-14.0 ± 2.7 mmHg) and HF rat (-12.4 ± 2.3). Chemerin mRNA was abolished in the liver and fats (primary producers of chemerin) from rats given the ASO chemerin vs control. Conclusion: A HF diet alone is insufficient to stimulate the dependence of blood pressure in the rat on chemerin.
RESUMEN
Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Yet, the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss. We hypothesized that increased activity in the subset of VTA DA neurons expressing neurotensin receptor-1 (NtsR1) might promote weight loss behaviors. To test this, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate VTA NtsR1 neurons in normal weight and diet-induced obese mice. Acute activation of VTA NtsR1 neurons (24hr) significantly decreased body weight in normal weight and obese mice by reducing food intake and increasing physical activity. Moreover, daily activation of VTA NtsR1 neurons in obese mice sustained weight loss over 7 days. Activating VTA NtsR1 neurons also suppressed how much mice worked to obtain sucrose rewards, even when there was high motivation to consume. However, VTA NtsR1 neural activation was not reinforcing, nor did it invoke liabilities associated with whole-body NtsR1 agonism such as anxiety, vasodepressor response or hypothermia. Activating VTA NtsR1 neurons therefore promotes dual behaviors that support weight loss without causing adverse effects, and is worth further exploration for managing obesity.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Receptores de Neurotensina/metabolismo , Área Tegmental Ventral/metabolismo , Pérdida de Peso/fisiología , Animales , Clozapina/análogos & derivados , Clozapina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Ratones , Obesidad/metabolismo , Recompensa , Área Tegmental Ventral/efectos de los fármacos , Pérdida de Peso/efectos de los fármacosRESUMEN
Vascular dysfunctions are observed in the arteries from hypertensive subjects. The establishment of the Dahl salt-sensitive (SS) male and female rat models to develop a reproducible hypertension with high-fat (HF) diet feeding from weaning allows addressing the question of whether HF diet-associated hypertension results in vascular dysfunction similar to that of essential hypertension in both sexes. We hypothesized that dysfunction of three distinct vascular layers, i.e., endothelial, smooth muscle, and perivascular adipose tissue (PVAT), would be present in the aorta from HF diet-fed versus control diet-fed male and female rats. Dahl SS rats were fed a control (10% kcal of fat) or HF (60%) diet from weaning for 24 wk. Male and female Dahl SS rats became equally hypertensive when placed on a HF diet. For male and female rats, the thoracic aorta exhibited medial hypertrophy in HF diet-induced hypertension versus control, but neither displayed a hyperresponsive contraction to the α-adrenergic agonist phenylephrine nor an endothelial cell dysfunction as measured by acetylcholine-induced relaxation. A beneficial PVAT function, support of stress relaxation, was reduced in the male versus female rats fed a HF diet. PVAT in the aorta of males but not in females retained the anticontractile activity. We conclude that this HF model does not display the same vascular dysfunctions observed in essential hypertension. Moreover, both male and female show significantly different vascular dysfunctions in this HF feeding model.NEW & NOTEWORTHY Although the aorta exhibits medial hypertrophy in response to HF diet-induced hypertension, it did not exhibit hyperresponsive contraction to an α-adrenergic agonist nor endothelial cell dysfunction; this was true for both sexes. Unlike other hypertension models, PVAT around aorta from (male) rats on the HF diet retained significant anticontractile activity. PVAT around aorta of the male on a HF diet was modestly more fibrotic and lost the ability to assist in arterial stress relaxation.
Asunto(s)
Tejido Adiposo/metabolismo , Aorta Torácica/fisiología , Dieta Alta en Grasa , Vasodilatación/fisiología , Acetilcolina/farmacología , Tejido Adiposo/efectos de los fármacos , Animales , Aorta Torácica/efectos de los fármacos , Femenino , Masculino , Ratas , Ratas Endogámicas Dahl , Factores Sexuales , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
Perivascular adipose tissue (PVAT) may connect adiposity to hypertension because of its vasoactive functions and proximity to blood vessels. We hypothesized that immune cell changes in PVATs precede the development of high fat diet (HFD)-induced hypertension. Both sexes of Dahl S rat become equally hypertensive when fed a HFD. Further, both sexes would have similar immune cell composition in PVATs with the development and progression of hypertension. Male and female Dahl S rats were fed a regular (10% calories from fat; CD) diet or a HFD (60%) from weaning. PVATs from around the thoracic aorta (APVAT) and small mesenteric vessels (MRPVAT) were harvested at 10 weeks (pre-hypertensive), 17 weeks (onset), or 24 (hypertensive) weeks on diet. RNA-sequencing in MRPVAT at 24 weeks indicated sex-differences with HFD (>CD) and diet-differences in males (>females). The top 2 out of 7 immune processes with the maximum number of differentially expressed genes (DEGs) were associated with immune effector processes and leukocyte activation. Macrophages and T cells (and their activation status), neutrophils, mast, B and NK cells were measured by flow cytometry. Sex-specific changes in the number of CD4 memory T cells (males > females) and M2-like macrophages (females > males) in PVATs occur with a HFD before hypertension developed. Sex-differences became more prominent with the development and progression of hypertension, driven by the diet (HFD > CD). These findings suggest that though the magnitudes of increased blood pressure were equivalent in both sexes, the associated phenotypic changes in the immune subsets within the PVATs were different in the male vs. the female with the development and progression of hypertension.
RESUMEN
Renal denervation (RDNX) lowers mean arterial pressure (MAP) in patients with resistant hypertension. Less well studied is the effect of celiac ganglionectomy (CGX), a procedure which involves the removal of the nerves innervating the splanchnic vascular bed. We hypothesized that RDNX and CGX would both lower MAP in genetically hypertensive Schlager (BPH/2J) mice through a reduction in sympathetic tone. Telemeters were implanted into the femoral artery in mice to monitor MAP before and after RDNX (n=5), CGX (n=6), or SHAM (n=6). MAP, systolic blood pressure, diastolic blood pressure, and heart rate were recorded for 14 days postoperatively. The MAP response to hexamethonium (10 mg/kg, IP) was measured on control day 3 and postoperative day 10 as a measure of global neurogenic pressor activity. The efficacy of denervation was assessed by measurement of tissue norepinephrine. Control MAP was similar among the 3 groups before surgical treatments (≈130 mm Hg). On postoperative day 14, MAP was significantly lower in RDNX (-11±2 mm Hg) and CGX (-11±1 mm Hg) groups compared with their predenervation values. This was not the case in SHAM mice (-5±3 mm Hg). The depressor response to hexamethonium in the RDNX group was significantly smaller on postoperative day 10 (-10±5 mm Hg) compared with baseline control (-25±10 mm Hg). This was not the case in mice in the SHAM (day 10; -28±5 mm Hg) or CGX (day 10; -34±7 mm Hg) group. In conclusion, both renal and splanchnic nerves contribute to hypertension in BPH/2J mice, but likely through different mechanisms.
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Presión Arterial/fisiología , Desnervación/métodos , Ganglionectomía/métodos , Hipertensión/cirugía , Riñón/inervación , Animales , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Hipertensión/genética , Hipertensión/fisiopatología , Masculino , Ratones , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
Perivascular adipose tissue (PVAT) modifies the contractile function of the vessel it surrounds (outside-in signaling). Little work points to the vessel actively affecting its surrounding PVAT. We hypothesized that inside-out arterial signaling to PVAT would be evidenced by the response of PVAT to changes in tangential vascular wall stress. Rats coarcted in the mid-thoracic aorta created PVAT tissues that would exemplify pressure-dependent changes (above vs. below coarctation); a sham rat was used as a control. Radiotelemetry revealed a â¼20 mmHg systolic pressure gradient across the coarctation 4 wk after surgery. Four measures (histochemical, adipocyte progenitor proliferation and differentiation, isometric tone, and bulk mRNA sequencing) were used to compare PVAT above versus below the ligature in sham and coarcted rats. Neither aortic collagen deposition in PVAT nor arterial media/radius ratio above coarctation was increased versus below segments. However, differentiated adipocytes derived from PVAT above the coarctation accumulated substantially less triglycerides versus those below; their relative proliferation rate as adipogenic precursors was not different. Functionally, the ability of PVAT to assist stress relaxation of isolated aorta was reduced in rings above versus below the coarctation. Transcriptomic analyses revealed that the coarctation resulted in more differentially expressed genes (DEGs) between PVAT above versus below when compared with sham samples from the same locations. A majority of DEGs were in PVAT below the coarctation and were enriched in neuronal/synaptic terms. These findings provide initial evidence that signaling from the vascular wall, as stimulated by a pressure change, influences the function and transcriptional profile of its PVAT.NEW & NOTEWORTHY A mid-thoracic aorta coarcted rat was created to generate a stable pressure difference above versus below the coarctation ligature. This study determined that the PVAT around the thoracic aorta exposed to a higher pressure has a significantly reduced ability to assist stress relaxation versus that below the ligature and appears to retain the ability to be anticontractile. At the same time, the PVAT around the thoracic aorta exposed to higher pressure had a reduced adipogenic potential versus that below the ligature. Transcriptomics analyses indicated that PVAT below the coarctation showed the greatest number of DEGs with an increased profile of the synaptic neurotransmitter gene network.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Aorta Torácica/fisiopatología , Coartación Aórtica/fisiopatología , Presión Arterial , Mecanotransducción Celular , Transcriptoma , Adipocitos/patología , Adipogénesis , Tejido Adiposo/patología , Animales , Coartación Aórtica/genética , Coartación Aórtica/metabolismo , Coartación Aórtica/patología , Proliferación Celular , Modelos Animales de Enfermedad , Redes Reguladoras de Genes , Masculino , Ratas Sprague-DawleyRESUMEN
In health, PVAT secretes anti-contractile factors that relax the underlying artery. PVAT's contributions to vascular function include more than production of vasoactive substances. We hypothesized that PVAT benefits the artery by assisting the function of stress (-induced) relaxation. Thoracic aorta rings from Sprague Dawley rats were mounted in isolated tissue baths with (+) and without (-) PVAT. A cumulative length tension (0-6 grams) was generated. The tension to which the tissue stress relaxed over 30 minutes was recorded; the tension lost was stress relaxation. The presence of PVAT increased the amount of stress relaxation (final tension in mgs; aortic ring -PVAT = 4578 ± 190; aortic ring + PVAT = 2730 ± 274, p < 0.05). PVAT left attached but not encompassing the aorta provided no benefit in cumulative stress relaxation (aortic ring +/- PVAT = 4122 ± 176; p > 0.05 vs -PVAT). A PVAT ring separated from the aorta demonstrated more profound stress relaxation than did the aortic ring itself. Finally, PVAT-assisted stress relaxation was observed in an artery with white fat (superior mesenteric artery) and in aorta from both male and female of another rat strain, the Dahl S rat. Knowledge of this new PVAT function supports PVAT as an essential player in vascular health.
Asunto(s)
Tejido Adiposo/fisiología , Aorta Torácica/fisiología , Vasodilatación/fisiología , Animales , Arterias Mesentéricas/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Since chemerin's identification as an adipokine, it has been associated with a number of human diseases including diabetes and obesity. However, the basic scientific foundation for these clinical determinations is still lacking. Fibroblastic mouse 3T3 cells are unable to develop lipid droplets if chemerin is not present. Thus, we hypothesized that an in vivo rat model chemerin knockout (KO; an advancement from the previously mentioned in vitro cultures) would have limited accumulation of lipid in adipocytes compared to their wild-type (WT) counterparts. Female WT/KO rats (Sprague Dawley background) were fed a low-fat diet starting at 8 weeks of age with weekly body weight and food consumption monitoring. At 25 weeks of age, adipose tissue depots were dissected and flash frozen for PCR analysis or fixed with paraformaldehyde for histology. Over the 17 weeks of experimentation, WT and KO animals did not have differences in total body weight or food consumption but KO animals had a significantly reduced amount of visceral fat compared to WT animals (via microCT at 8 and 25 weeks). Histology of retroperitoneal and mesenteric depots demonstrated a significant leftward shift in adipocyte size in the mesenteric but not the retroperitoneal depot of the KO compared to WT animals. Similarly, in the mesenteric fat of the KO rat, gene expression of adiponectin, fatty acid synthase, perilipin, and leptin were significantly reduced compared to mesenteric fat of WT animals and retroperitoneal fat of both WT and KO animals. Adiponectin was highlighted by a protein-protein interaction network as being important for the physiological effects of chemerin removal. These data are the first, to our knowledge, to demonstrate chemerin's adipokine potential in vivo and identify it as fat depot location-specific.
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Adipogénesis/genética , Quimiocinas/análisis , Adipocitos/fisiología , Adipoquinas/fisiología , Tejido Adiposo/citología , Animales , Peso Corporal , Quimiocinas/genética , Quimiocinas/fisiología , Dieta con Restricción de Grasas , Técnicas de Inactivación de Genes , Grasa Intraabdominal , Gotas Lipídicas , Mesenterio/citología , Ratas , Ratas Sprague-DawleyRESUMEN
Obesity hypertension is driven by sympathetic neurotransmission to the heart and blood vessels. We tested the hypothesis that high-fat diet (HFD)-induced hypertension is driven by sympathetic neurotransmission to mesenteric arteries (MA) in male but not female Dahl salt-sensitive (Dahl ss) rat. Rats were fed a control diet (CD; 10â¯kcal% from fat) or HFD (60â¯kcal% from fat) beginning at 3â¯weeks (wk) of age; measurements were made at 10-, 17- and 24-wk. Body weight increased with HFD, age and sex. Mean arterial pressure (MAP) was higher in HFD versus CD rats from both sexes at 17- and 24-wk. MA constriction measured using pressure myography, and electrical field stimulation (EFS, 0.2-30â¯Hz) was greater in HFD versus CD in males at 17-wk; this was not due to changes in α2 autoreceptor or norepinephrine transporter (NET) function. Prazosin (α1-AR antagonist) and suramin (P2 receptor antagonist) inhibited neurogenic MA constriction equally in all groups. Arterial reactivity to exogenous norepinephrine (NE; 10-8 - 10-5â¯M) was lower in HFD versus CD at 10-wk in males. Female MA reactivity to exogenous ATP was lower at 24-weeks compared to earlier time points. HFD did not affect tyrosine hydroxylase (TH) or the vesicular nucleotide transporter (VNUT) nerve density in MA from both sexes. NE content was lower in MA but higher in plasma at 24-wk compared to 10- and 17-wk in both sexes. In conclusion, HFD-induced hypertension is not driven by increased sympathetic neurotransmission to MA in male and female Dahl ss rats.
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Dieta Alta en Grasa , Hipertensión/fisiopatología , Arterias Mesentéricas/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Transmisión Sináptica/fisiología , Factores de Edad , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Hipertensión/etiología , Hipertensión/metabolismo , Masculino , Arterias Mesentéricas/efectos de los fármacos , Ratas , Ratas Endogámicas Dahl , Factores Sexuales , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
Chemerin is a contractile adipokine, produced in liver and fat, and removal of the protein by antisense oligonucleotides (ASO) lowers blood pressure in the normal Sprague Dawley rat. In humans, chemerin is positively associated with blood pressure and obesity so we hypothesized that in a model of hypertension derived from high-fat (HF) feeding, the chemerin ASO would reduce blood pressure more than a high-salt (HS) model. Male Dahl S rats were given a HF (60% kcal fat; age 3-24 wk) or HS diet (4% salt; age 20-24 wk to match age and blood pressure of HF animals). Scrambled control, whole body, or liver-specific ASOs that knock down chemerin were delivered subcutaneously once per week for 4 wk with tissue and blood collected 2 days after the last injection. Conscious blood pressure was measured 24 h/day by radiotelemetry. By the end of whole body ASO administration, blood pressure of HF animals had fallen 29 ± 2 mmHg below baseline, while blood pressure of HS-diet animals fell by only 12 ± 4 mmHg below baseline. Administration of a liver-specific ASO to HF Dahl S resulted in a 6 ± 2 mmHg fall in blood pressure below baseline. Successful knockdown of chemerin in both the whole body and liver-specific administration was confirmed by Western and PCR. These results suggest that chemerin, not derived from liver but potentially from adipose tissue, is an important driver of hypertension associated with high fat. This knowledge could lead to the development of antihypertensive treatments specifically targeted to obesity-associated hypertension.
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Presión Sanguínea/efectos de los fármacos , Quimiocinas/antagonistas & inhibidores , Grasas de la Dieta/farmacología , Oligonucleótidos Antisentido/farmacología , ARN Mensajero/antagonistas & inhibidores , Cloruro de Sodio Dietético/farmacología , Tejido Adiposo/metabolismo , Animales , Quimiocinas/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas , Ratas Endogámicas DahlRESUMEN
We examined the impact of sex on high-fat diet (HFD)-induced renal alterations in Dahl salt-sensitive and Sprague Dawley rats. In Dahl rats, HFD (60% kcal from fat for 24-26 weeks starting at weaning) significantly and equally increased blood pressure in males and females when compared with rats fed a control diet (10% kcal from fat). Male Dahl rats on HFD exhibited progressive renal histological injury and moderately increased renal macrophage infiltration at 10 and 24 weeks of feeding when compared with males on control diet. Female Dahl rats had lower grade renal injury and less macrophage infiltration (except at 17 weeks) than males regardless of diet. Male Dahl rats on both diets showed progressively increasing numbers of renal T-cells, a pattern not observed in females. HFD per se did not significantly affect renal T-cell number. Male Dahl rats had lower renal regulatory T-cells cell ratio than females at 24 weeks. Renal macrophage and T-cell infiltrations were highly correlated to final mean arterial pressure levels in males but not in females. Sprague Dawley rats fed HFD were normotensive without significant renal injury/inflammation after 24 weeks of feeding. In summary, HFD feeding fails to increase arterial blood pressure in Sprague Dawley rats but strongly promotes hypertension in both male and female Dahl salt-sensitive rats. Only Dahl males, however, exhibited blood pressure-associated renal inflammation and injury. Maintenance of regulatory T-cells ratio may protect against hypertension-associated renal injury/inflammation but not HFD-induced hypertension.
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Presión Sanguínea/fisiología , Dieta Alta en Grasa , Inflamación/patología , Riñón/patología , Caracteres Sexuales , Animales , Femenino , Masculino , Ratas , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Cloruro de Sodio Dietético , Linfocitos T Reguladores/patologíaRESUMEN
Measures of the adipokine chemerin are elevated in multiple cardiovascular diseases, including hypertension, but little mechanistic work has been done to implicate chemerin as being causative in such diseases. The chemerin knockout (KO) rat was created to test the hypothesis that removal of chemerin would reduce pressure in the normal and hypertensive state. Western analyses confirmed loss of chemerin in the plasma and tissues of the KO vs. wild-type (WT) rats. Chemerin concentration in plasma and tissues was lower in WT females than in WT males, as determined by Western analysis. Conscious male and female KO rats had modest differences in baseline measures vs. the WT that included systolic, diastolic, mean arterial and pulse pressures, and heart rate, all measured telemetrically. The mineralocorticoid deoxycorticosterone acetate (DOCA) and salt water, combined with uninephrectomy as a hypertensive stimulus, elevated mean and systolic blood pressures of the male KO higher than the male WT. By contrast, all pressures in the female KO were lower than their WT throughout DOCA-salt treatment. These results revealed an unexpected sex difference in chemerin expression and the ability of chemerin to modify blood pressure in response to a hypertensive challenge.-Watts, S. W., Darios, E. S., Mullick, A. E., Garver, H., Saunders, T. L., Hughes, E. D., Filipiak, W. E., Zeidler, M. G., McMullen, N., Sinal, C. J., Kumar, R. K., Ferland, D. J., Fink, G. D. The chemerin knockout rat reveals chemerin dependence in female, but not male, experimental hypertension.
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Renal sympathetic activity affects blood pressure in part by increasing renovascular resistance via release of norepinephrine (NE) from sympathetic nerves onto renal arteries. Here we test the idea that adipose tissue adjacent to renal blood vessels, i.e. renal perivascular adipose tissue (RPVAT), contains a pool of NE which can be released to alter renal vascular function. RPVAT was obtained from around the main renal artery/vein of the male Sprague Dawley rats. Thoracic aortic PVAT and mesenteric PVAT also were studied as brown-like and white fat comparators respectively. RPVAT was identified as a mix of white and brown adipocytes, because of expression of both brown-like (e.g. uncoupling protein 1) and white adipogenic genes. All PVATs contained NE (ng/g tissue, RPVAT:524⯱â¯68, TAPVAT:740⯱â¯16, MPVAT:96⯱â¯24). NE was visualized specifically in RPVAT adipocytes by immunohistochemistry. The presence of RPVAT (+RPVAT) did not alter the response of isolated renal arteries to NE compared to responses of arteries without RPVAT (-RPVAT). By contrast, the maximum contraction to the sympathomimetic tyramine was ~2× greater in the renal artery +PVAT versus -PVAT. Tyramine-induced contraction in +RPVAT renal arteries was reduced by the α1-adrenoceptor antagonist prazosin and the NE transporter inhibitor nisoxetine. These results suggest that tyramine caused release of NE from RPVAT. Renal denervation significantly (>50%) reduced NE content of RPVAT but did not modify tyramine-induced contraction of +RPVAT renal arteries. Collectively, these data support the existence of a releasable pool of NE in RPVAT that is independent of renal sympathetic innervation and has the potential to change renal arterial function.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Norepinefrina/metabolismo , Comunicación Paracrina , Arteria Renal/metabolismo , Venas Renales/metabolismo , Vasoconstricción , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/inervación , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/inervación , Animales , Relación Dosis-Respuesta a Droga , Masculino , Comunicación Paracrina/efectos de los fármacos , Ratas Sprague-Dawley , Arteria Renal/efectos de los fármacos , Arteria Renal/inervación , Venas Renales/inervación , Transducción de Señal , Simpatectomía , Sistema Nervioso Simpático/fisiología , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
DOCA-salt and obesity-related hypertension are associated with inflammation and sympathetic nervous system hyperactivity. Prejunctional α2-adrenergic receptors (α2ARs) provide negative feedback to norepinephrine release from sympathetic nerves through inhibition of N-type Ca2+ channels. Increased neuronal norepinephrine release in DOCA-salt and obesity-related hypertension occurs through impaired α2AR signaling; however, the mechanisms involved are unclear. Mesenteric arteries are resistance arteries that receive sympathetic innervation from the superior mesenteric and celiac ganglia (SMCG). We tested the hypothesis that macrophages impair α2AR-mediated inhibition of Ca2+ channels in SMCG neurons from DOCA-salt and high-fat diet (HFD)-induced hypertensive rats. Whole cell patch-clamp methods were used to record Ca2+ currents from SMCG neurons maintained in primary culture. We found that DOCA-salt, but not HFD-induced, hypertension caused macrophage accumulation in mesenteric arteries, increased SMCG mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α, and impaired α2AR-mediated inhibition of Ca2+ currents in SMCG neurons. α2AR dysfunction did not involve changes in α2AR expression, desensitization, or downstream signaling factors. Oxidative stress impaired α2AR-mediated inhibition of Ca2+ currents in SMCG neurons and resulted in receptor internalization in human embryonic kidney-293T cells. Systemic clodronate-induced macrophage depletion preserved α2AR function and lowered blood pressure in DOCA-salt rats. HFD caused hypertension without obesity in Sprague-Dawley rats and hypertension with obesity in Dahl salt-sensitive rats. HFD-induced hypertension was not associated with inflammation in SMCG and mesenteric arteries or α2AR dysfunction in SMCG neurons. These results suggest that macrophage-mediated α2AR dysfunction in the mesenteric circulation may only be relevant to mineralocorticoid-salt excess. NEW & NOTEWORTHY Here, we identify a contribution of macrophages to hypertension development through impaired α2-adrenergic receptor (α2AR)-mediated inhibition of sympathetic nerve terminal Ca2+ channels in DOCA-salt hypertensive rats. Impaired α2AR function may involve oxidative stress-induced receptor internalization. α2AR dysfunction may be unique to mineralocorticoid-salt excess, as it does not occur in obesity-related hypertension.
Asunto(s)
Fibras Adrenérgicas/metabolismo , Canales de Calcio Tipo N/metabolismo , Acetato de Desoxicorticosterona , Dieta Alta en Grasa , Hipertensión/metabolismo , Macrófagos/metabolismo , Arterias Mesentéricas/inervación , Receptor Cross-Talk , Receptores Adrenérgicos alfa 2/metabolismo , Cloruro de Sodio Dietético , Animales , Presión Arterial , Señalización del Calcio , Modelos Animales de Enfermedad , Retroalimentación Fisiológica , Células HEK293 , Humanos , Hipertensión/etiología , Hipertensión/fisiopatología , Mediadores de Inflamación/metabolismo , Masculino , Norepinefrina/metabolismo , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/genéticaRESUMEN
Previously, we demonstrated that chronic exposure to low levels of estradiol-17ß (E2) increases mean arterial pressure (MAP) in young female Sprague-Dawley (SD) rats, however, the underlying mechanisms are unclear. Since endothelin-1 (ET-1) is implicated in blood pressure (BP) regulation, we hypothesized that E2's effects on MAP are mediated through central ET-1. To test this, young female SD rats were either sham implanted or implanted s.c. with slow-release E2 pellets (20 ng/day for 90 days). BP was monitored by telemetry. After 75 days of E2 exposure, ETA antagonist or vehicle was administered i.c.v. After 90 days of E2 exposure, rats were sacrificed, and the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) were microdissected for gene expression and protein analysis of ET-1 and its receptors. E2 exposure increased MAP after pellet implantation. Gene expression of ET-1 and ETA but not ETB receptors were upregulated in the PVN and RVLM of E2 treated animals. Further, the protein levels of ETA receptor were also increased in the PVN of E2 treated animals. However, i.c.v. infusion of the ETA antagonist did not completely block the increase in blood pressure. Our results suggest that increases in central ET-1 activity could possibly play a role in chronic E2-induced increase in BP but further studies are needed to completely understand the contribution of ET-1 in this phenomenon.
Asunto(s)
Endotelina-1/genética , Endotelina-1/metabolismo , Estradiol/toxicidad , Antagonistas de Estrógenos/administración & dosificación , Hipertensión/inducido químicamente , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/genética , Hipertensión/metabolismo , Bulbo Raquídeo/química , Bulbo Raquídeo/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/química , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Estradiol/genética , Receptores de Estradiol/metabolismo , Pruebas de Toxicidad CrónicaRESUMEN
OBJECTIVE: Chronic hypertension induces detrimental changes in the structure and function of surface cerebral arteries. Very little is known about PAs, which perfuse distinct neuronal populations in the cortex and may play a role in cerebrovascular disorders. We investigated the effect of DOCA-salt induced hypertension on endothelial function and artery structure in PAs and MCAs. METHODS: Uninephrectomized male Sprague-Dawley rats were implanted with a subcutaneous pellet containing DOCA (150 mg/kg b.w.) and drank salt water (1% NaCl and 0.2% KCl) for 4 weeks. Sham rats were uninephrectomized and drank tap water. Vasoreactivity and passive structure in the MCAs and the PAs were assessed by pressure myography. RESULTS: Both MCAs and PAs from DOCA-salt rats exhibited impaired endothelium-dependent dilation (P<.05). In the PAs, addition of NO and COX inhibitors enhanced dilation in DOCA-salt rats (P<.05), suggesting that dysfunctional NO and COX-dependent signaling could contribute to impaired endothelium-mediated dilation. MCAs from DOCA-salt rats exhibited inward remodeling (P<.05). CONCLUSIONS: Hypertension-induced MCA remodeling coupled with impaired endothelium-dependent dilation in both the MCAs and PAs may exacerbate the risk of cerebrovascular accidents and the associated morbidity and mortality.
Asunto(s)
Arterias Cerebrales/fisiopatología , Hipertensión/fisiopatología , Animales , Arteriolas/fisiopatología , Inhibidores de la Ciclooxigenasa/farmacología , Acetato de Desoxicorticosterona/farmacología , Endotelio Vascular , Hipertensión/inducido químicamente , Masculino , Arteria Cerebral Media/fisiopatología , Miografía/métodos , Óxido Nítrico/farmacología , Tejido Parenquimatoso/irrigación sanguínea , Ratas , Ratas Sprague-Dawley , Vasodilatación/efectos de los fármacosRESUMEN
Artery remodeling, described as a change in artery structure, may be responsible for the increased risk of cardiovascular disease with aging. Although the risk for stroke is known to increase with age, relatively young animals have been used in most stroke studies. Therefore, more information is needed on how aging alters the biomechanical properties of cerebral arteries. Posterior cerebral arteries (PCAs) and parenchymal arterioles (PAs) are important in controlling brain perfusion. We hypothesized that aged (22-24 mo old) C57bl/6 mice would have stiffer PCAs and PAs than young (3-5 mo old) mice. The biomechanical properties of the PCAs and PAs were assessed by pressure myography. Data are presented as means ± SE of young vs. old. In the PCA, older mice had increased outer (155.6 ± 3.2 vs. 169.9 ± 3.2 µm) and lumen (116.4 ± 3.6 vs. 137.1 ± 4.7 µm) diameters. Wall stress (375.6 ± 35.4 vs. 504.7 ± 60.0 dyn/cm(2)) and artery stiffness (ß-coefficient: 5.2 ± 0.3 vs. 7.6 ± 0.9) were also increased. However, wall strain (0.8 ± 0.1 vs. 0.6 ± 0.1) was reduced with age. In the PAs from old mice, wall thickness (3.9 ± 0.3 vs. 5.1 ± 0.2 µm) and area (591.1 ± 95.4 vs. 852.8 ± 100 µm(2)) were increased while stress (758.1 ± 100.0 vs. 587.2 ± 35.1 dyn/cm(2)) was reduced. Aging also increased mean arterial and pulse pressures. We conclude that age-associated remodeling occurs in large cerebral arteries and arterioles and may increase the risk of cerebrovascular disease.