Influence of Vitamin D on the Vasoactive Effect of Estradiol in a Rat Model of Polycystic Ovary Syndrome

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D- animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.

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Lower-limb veins are thicker and vascular reactivity is decreased in a rat PCOS model: concomitant vitamin D3 treatment partially prevents these changes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01024.2013 ◽

2014 ◽

Vol 307 (6) ◽

pp. H848-H857 ◽

Cited By ~ 6

Author(s):

Szabolcs Várbíró ◽

Levente Sára ◽

Péter Antal ◽

Anna Monori-Kiss ◽

Anna-Mária Tőkés ◽

...

Keyword(s):

Vascular Reactivity ◽

Mechanical Load ◽

Polycystic Ovary ◽

Varicose Veins ◽

Saphenous Veins ◽

Female Wistar Rats ◽

Cox 2 ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Polycystic ovary syndrome (PCOS) causes vascular damage to arteries; however, there are no data for its effect on veins. Our aim was to clarify the effects of dihydrotestosterone (DHT)-induced PCOS both on venous biomechanics and on pharmacological reactivity in a rat model and to test the possible modulatory role of vitamin D3 (vitD). PCOS was induced in female Wistar rats by DHT treatment (83 μg/day, subcutaneous pellet). After 10 wk, the venous biomechanics, norepinephrine (NE)-induced contractility, and acetylcholine-induced relaxation were tested in saphenous veins from control animals and from animals treated with DHT or DHT with vitD using pressure angiography. Additionally, the expression levels of endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX-2) were measured using immunohistochemistry. Increased diameter, wall thickness, and distensibility as well as decreased vasoconstriction were detected after the DHT treatment. Concomitant vitD treatment lowered the mechanical load on the veins, reduced distensibility, and resulted in vessels that were more relaxed. Although there was no difference in the endothelial dilation tested using acetylcholine (ACh), the blocking effect of NG-nitro-l-arginine methyl ester (l-NAME) was lower and was accompanied by lower COX-2 expression in the endothelium after the DHT treatment. Supplementation with vitD prevented these alterations. eNOS expression did not differ among the three groups. We conclude that the hyperandrogenic state resulted in thicker vein walls. These veins showed early remodeling and altered vasorelaxant mechanisms similar to those of varicose veins. Alterations caused by the chronic DHT treatment were prevented partially by concomitant vitD administration.

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Effect of Vitamin D Status on Vascular Function of the Aorta in a Rat Model of PCOS

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8865979 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

K. Lajtai ◽

R. Tarszabó ◽

B. Bányai ◽

B. Péterffy ◽

D. Gerszi ◽

...

Keyword(s):

Vitamin D ◽

Rat Model ◽

Vascular Function ◽

Polycystic Ovary ◽

Vascular Dysfunction ◽

Vitamin D Supplementation ◽

Female Rats ◽

Vitamin D Status ◽

Nitrative Stress ◽

Contraction And Relaxation

Polycystic ovary syndrome (PCOS) is associated with elevated cardiovascular risk. Early vascular dysfunction may lead to the development of cardiovascular disease in PCOS. Vitamin D deficiency (VDD) is a common comorbidity of PCOS that contributes to the pathogenesis of the disease and its complications. Both PCOS and VDD are accompanied by increased oxidative stress that may be involved in the arising vascular dysfunction. We aimed to investigate the role of vitamin D status on aortic function. PCOS was induced by an 8-week-long transdermal testosterone treatment of female rats, and low and adequate vitamin D status was achieved by dietary means. Contraction and relaxation abilities of isolated aortic segments were measured by myograph. Resorcin-fuchsin staining and immunohistochemical labeling of 3-nitrotyrosine were performed. No difference was shown in the norepinephrine-induced contraction of the aortas of different groups, whereas we detected reduced acetylcholine- and insulin-evoked relaxation in VDD groups. A lower level of resorcin-fuchsin staining and elevated 3-nitrotyrosine immunostaining was observed in VDD. In our study, we demonstrated early endothelial dysfunction in VDD PCOS rat model. Vitamin D supplementation could prevent vascular disturbances, while VDD itself damaged endothelium-dependent vasorelaxation and induced nitrative stress.

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Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes

Diabetologia ◽

10.1007/s00125-008-1159-9 ◽

2008 ◽

Vol 51 (12) ◽

pp. 2325-2332 ◽

Cited By ~ 25

Author(s):

A. Riad ◽

D. Westermann ◽

S. Van Linthout ◽

Z. Mohr ◽

S. Uyulmaz ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Rat Model ◽

Endothelial Nitric Oxide Synthase ◽

Vascular Dysfunction ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00367.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. R1114-R1121 ◽

Cited By ~ 30

Author(s):

Monica Longo ◽

Venu Jain ◽

Yuri P. Vedernikov ◽

Radek Bukowski ◽

Robert E. Garfield ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Vascular Function ◽

Vascular Dysfunction ◽

Mesenteric Arteries ◽

Fetal Origins ◽

Uterine Environment ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Epidemiological studies have shown increased incidence of hypertension and coronary artery disease in growth-restricted fetuses during their adult life. A novel animal model was used to test the hypothesis regarding the role of an abnormal uterine environment in fetal programming of adult vascular dysfunction. Mice lacking a functional endothelial nitric oxide synthase (NOS3−/−KO, where KO is knockout) and wild-type (WT) mice (NOS3+/+WT) were crossbred to produce homozygous NOS3−/−KO, maternally derived heterozygous (NOS3+/−mat, mother with NOS3 deficiency), paternally derived heterozygous (NOS3+/−pat, normal mother), and NOS3+/+WT litters. Number of fetuses per litter was smaller in NOS3−/−KO and NOS3+/−mat compared with NOS3+/−pat and NOS3+/+WT mice. Adult female mice from these litters (7–8 wk old) were killed, and ring preparations of carotid and mesenteric arteries were mounted in a wire myograph to evaluate the passive and reactive vascular characteristics. Slope of the length-tension plot (a measure of vascular compliance) was increased, and optimal diameter (as calculated by Laplace equation) was decreased in NOS3−/−KO and NOS3+/−mat compared with NOS3+/−pat and NOS3+/+WT mice. Acetylcholine caused vasorelaxation in NOS3+/−pat and NOS3+/+WT and contraction in NOS3−/−KO and NOS3+/−mat mice. Responses to phenylephrine and Ca2+ were increased in NOS3−/−KO and NOS3+/−mat compared with NOS3+/−pat and NOS3+/+WT mice. Relaxation to isoproterenol was decreased in NOS3−/−KO and NOS3+/−mat vs. NOS3+/−pat and NOS3+/+WT mice. Abnormalities in the passive and reactive in vitro vascular properties seen in NOS+/−mat that developed in a NOS3-deficient maternal/uterine environment compared with the genetically identical NOS3+/−pat mice that developed in a normal environment are the first direct evidence in support of a role for uterine environment in determining vascular function in later life.

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Differential expression of α2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01074.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. H135-H148 ◽

Cited By ~ 40

Author(s):

Tsuneo Kobayashi ◽

Takayuki Matsumoto ◽

Kazuyuki Ooishi ◽

Katsuo Kamata

Keyword(s):

Vascular Reactivity ◽

Matched Control ◽

Early Stage ◽

Vascular Dysfunction ◽

Spontaneous Diabetes ◽

Relaxation Response ◽

No Production ◽

Gk Rats ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

The aim of the present study was to compare vascular dysfunction between the early (12 wk old) and later (36 wk old) stages of spontaneous diabetes in Goto-Kakizaki (GK) rats. We also evaluated the aortic expression of the α2D-adrenoceptor and endothelial nitric oxide synthase (eNOS). Vascular reactivity was assessed in thoracic aortas from age-matched control rats and 12- and 36-wk GK rats. Using RT-PCR and immunoblots, we also examined the changes in expression of the α2D-adrenoceptor and eNOS. In aortas from GK rats (vs. those from age-matched control rats): 1) the relaxation response to ACh was enhanced at 12 wk but decreased at 36 wk; 2) the relaxation response to sodium nitroprusside was decreased at both 12 and 36 wk, 3) norepinephrine (NE)-induced contractility was decreased at 12 wk but not at 36 wk, 4) the expressions of α1B- and α1D-adrenoceptors were unaffected, whereas those of α2D-adrenoceptor and eNOS mRNAs were increased at both 12 and 36 wk; and 5) NE- and ACh-stimulated NOx (nitrite and nitrate) levels were increased at 12 wk, although at 36 wk ACh-stimulated NOx was lower, whereas NE-stimulated NOx showed no change. These results clearly demonstrate that enhanced ACh-induced relaxation and impaired NE-induced contraction, due to NO overproduction via eNOS and increased α2D-adrenoceptor expression, occur in early-stage GK rats and that the impaired ACh-induced relaxation in later-stage GK rats is due to reductions in both NO production and NO responsiveness (but not in eNOS expression).

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Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide

Journal of Applied Physiology ◽

10.1152/jappl.2002.92.1.33 ◽

2002 ◽

Vol 92 (1) ◽

pp. 33-40 ◽

Cited By ~ 15

Author(s):

Daniel Nyhan ◽

Soonyul Kim ◽

Stacey Dunbar ◽

Dechun Li ◽

Artin Shoukas ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Lung Tissue ◽

Rat Model ◽

Orthostatic Intolerance ◽

Volume Distribution ◽

Contractile Responses ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N G-nitro-l-arginine methyl ester (10−5 M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.

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In vivo gene transfer of endothelial nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits enhances endothelium-dependent relaxations but does not reverse vascular dysfunction

Atherosclerosis ◽

10.1016/s0021-9150(99)80224-x ◽

1999 ◽

Vol 144 ◽

pp. 58

Author(s):

T. O'Brien ◽

J. Sato ◽

T. Mohasci ◽

A. Noel ◽

P. Gloviczki ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Gene Transfer ◽

Endothelial Nitric Oxide Synthase ◽

Carotid Arteries ◽

Vascular Dysfunction ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

In Vivo Gene Transfer

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Aging induces muscle-specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries

Journal of Applied Physiology ◽

10.1152/japplphysiol.00461.2002 ◽

2002 ◽

Vol 93 (5) ◽

pp. 1685-1690 ◽

Cited By ~ 79

Author(s):

Christopher R. Woodman ◽

Elmer M. Price ◽

M. Harold Laughlin

Keyword(s):

Skeletal Muscle ◽

Mrna Expression ◽

Vascular Function ◽

Fischer 344 ◽

Old Rats ◽

The Right ◽

Oxide Synthase ◽

Endothelial Nitric Oxide ◽

Feed Arteries ◽

Skeletal Muscle Feed Arteries

We tested the hypothesis that aging decreases endothelium-dependent vasodilation in feed arteries perfusing rat skeletal muscle. In addition, we tested the hypothesis that attenuated vasodilator responses are associated with decreased endothelial nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) expression. Soleus feed arteries (SFA) and gastrocnemius feed arteries (GFA) were isolated from young (4 mo) and old (24 mo) male Fischer 344 rats. Feed arteries from the right hindlimb were cannulated with two glass micropipettes for examination of endothelium-dependent [acetylcholine (ACh)] and endothelium-independent [adenosine (Ado) or sodium nitroprusside (SNP)] vasodilator function. Feed arteries from the left hindlimb were frozen and used to assess eNOS and SOD-1 protein and mRNA expression. In SFA, endothelium-dependent dilation to ACh was reduced in old rats (0.9 ± 0.04 vs. 0.8 ± 0.03), whereas dilator responses to Ado and SNP were similar in SFA of young and old rats. In GFA, vasodilator responses to ACh, Ado, and SNP were not altered by age. eNOS and SOD-1 protein expression declined with age in SFA (−71 and −54%, respectively) but not in GFA. eNOS and SOD-1 mRNA expression were not altered by age in SFA or GFA. Collectively, these data indicate aging induces muscle-specific impairment of endothelium-dependent vascular function in SFA.

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