A sex‐specific, COX‐derived/thromboxane receptor activator causes depolarization and vasoconstriction in male mice mesenteric resistance arteries

Objective— Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. Approach and Results— Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. Conclusions— Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.

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Opioids Cause Sex-Specific Vascular Changes via Cofilin-Extracellular Signal-Regulated Kinase Signaling: Female Mice Present Higher Risk of Developing Morphine-Induced Vascular Dysfunction than Male Mice

Journal of Vascular Research ◽

10.1159/000517555 ◽

2021 ◽

pp. 1-11

Author(s):

Soyoung Cheon ◽

Jeremy C. Tomcho ◽

Jonnelle M. Edwards ◽

Nicole R. Bearss ◽

Emily Waigi ◽

...

Keyword(s):

Vascular Dysfunction ◽

Actin Dynamics ◽

Male Mice ◽

Resistance Arteries ◽

Opioid Use ◽

Female Mice ◽

Extracellular Signal ◽

Increased Risk ◽

Vascular Age ◽

Pulmonary Arterial

Recent studies have shown that chronic use of prescription or illicit opioids leads to an increased risk of cardiovascular events and pulmonary arterial hypertension. Indices of vascular age and arterial stiffness are also shown to be increased in opioid-dependent patients, with the effects being more marked in women. There are currently no studies investigating sex-specific vascular dysfunction in opioid use, and the mechanisms leading to opioid-induced vascular damage remain unknown. We hypothesized that exposure to exogenous opioids causes sex-specific vascular remodeling that will be more pronounced in female. Acknowledging the emerging roles of cofilins and extracellular signal-regulated kinases (ERKs) in mediating actin dynamics, we investigated the effects of morphine on these molecules. Twenty-four hour exposure to morphine increased inactivated cofilin and activated ERKs in resistance arteries from female mice, which may promote stress fiber over-assembly. We also performed continuous intraluminal infusion of morphine in pressurized resistance arteries from male and female mice using culture pressure myographs. We observed that morphine reduced the vascular diameter in resistance arteries from female, but not male mice. These results have significant implications for the previously unexplored role of exogenous opioids as a modifiable cardiovascular risk factor, especially in women.

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Effect of aging and hypertension on contractility of resistance arteries: modulation by endothelial factors

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.3.h837 ◽

1995 ◽

Vol 269 (3) ◽

pp. H837-H844 ◽

Cited By ~ 8

Author(s):

M. G. Lang ◽

G. Noll ◽

T. F. Luscher

Keyword(s):

Isometric Tension ◽

No Production ◽

Ang Ii ◽

Resistance Arteries ◽

Spontaneously Hypertensive ◽

Thromboxane Receptor ◽

Increased Sensitivity ◽

Wistar Kyoto ◽

Thromboxane Receptor Antagonist ◽

Effects Of Aging

The effects of aging and hypertension on contraction were examined in rat mesenteric resistance arteries of 12- and 74-wk-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The vessels were suspended in myographs (37 degrees C, 95% O2-5% CO2) filled with modified Krebs-Ringer bicarbonate solution. Isometric tension was measured. Contractions to KCl (100 mM) were similar in adult WKY and SHR; they increased in senescent WKY (P < 0.05) but decreased in senescent SHR (P < 0.05). Responses to norepinephrine (% of KCl) were comparable in all four groups. However, blockade of nitric oxide (NO) production with NG-nitro-L-arginine methyl ester (L-NAME) enhanced the sensitivity to norepinephrine in senescent animals, particularly in SHR. Inhibition of cyclooxygenase with indomethacin prevented increased sensitivity to norepinephrine after NO blockade. Responses to angiotensin (ANG) II were not affected by aging and hypertension, but the thromboxane receptor antagonist SQ-30741 reduced ANG II-induced contractions only in SHR of both ages (P < 0.05). Aging increased responses to ANG I in SHR but decreased it in WKY (P < 0.05). In quiescent rings with endothelium, acetylcholine caused contractions in the presence of L-NAME in adult and senescent SHR but not in WKY (P < 0.05). SQ-30741 prevented these contractions (P < 0.05). Contractions to the thromboxane analogue U-46619 were reduced only in senescent SHR (P < 0.05). Thus aging increases and hypertension decreases contractility of smooth muscle in rat mesenteric resistance arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

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Estrogen receptor alpha, but not estrogen receptor beta, is involved in the regulation of the OPG/RANKL (osteoprotegerin/receptor activator of NF-kappa B ligand) ratio and serum interleukin-6 in male mice

Journal of Endocrinology ◽

10.1677/joe.0.1710425 ◽

2001 ◽

Vol 171 (3) ◽

pp. 425-433 ◽

Cited By ~ 63

Author(s):

MK Lindberg ◽

M Erlandsson ◽

SL Alatalo ◽

S Windahl ◽

G Andersson ◽

...

Keyword(s):

Estrogen Receptor ◽

Interleukin 6 ◽

Serum Levels ◽

Tartrate Resistant Acid Phosphatase ◽

Male Mice ◽

Mineral Density ◽

Nf Kappa B ◽

Receptor Activator ◽

Trap 5B ◽

Er Alpha

Estrogens are important for the male skeleton. Osteoprotegerin (OPG), receptor activator of NF-kappa B ligand (RANKL), interleukin-6 (IL-6), IL-1 and tumor necrosis factor alpha (TNFalpha) have been suggested to be involved in the skeletal effects of estrogen. We treated orchidectomized mice with estradiol for 2 weeks and observed a 143% increase in the trabecular bone mineral density of the distal metaphysis of femur that was associated with a decreased OPG/RANKL mRNA ratio in vertebral bone. A similar decreased OPG/RANKL ratio was also seen after estrogen treatment of ovariectomized female mice. The effect of estrogen receptor (ER) inactivation on the OPG/RANKL ratio was dissected by using intact male mice lacking ER alpha (ERKO), ER beta (BERKO) or both receptors (DERKO). The expression of OPG was increased in ERKO and DERKO but not in BERKO male mice, resulting in an increased OPG/RANKL ratio. Furthermore, serum levels of IL-6 and tartrate-resistant acid phosphatase 5b (TRAP 5b) were decreased in ERKO and DERKO, but not in BERKO male mice. These results demonstrate that ER alpha, but not ER beta, is involved in the regulation of the vertebral OPG/RANKL ratio, serum levels of IL-6 and TRAP 5b in male mice.

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Ultrastructural Lesions Produced by Alcohol and Sucrose in the Heart and Liver of C57BL Mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100068035 ◽

1970 ◽

Vol 28 ◽

pp. 208-209

Author(s):

K.K. SEKHRI ◽

C.S. ALEXANDER ◽

H.T. NAGASAWA

Keyword(s):

Osmium Tetroxide ◽

Male Mice ◽

Alcohol Group ◽

Group Iii ◽

Group I ◽

C57bl Mice ◽

Group Ii

C57BL male mice (Jackson Lab., Bar Harbor, Maine) weighing about 18 gms were randomly divided into three groups: group I was fed sweetened liquid alcohol diet (modified Schenkl) in which 36% of the calories were derived from alcohol; group II was maintained on a similar diet but alcohol was isocalorically substituted by sucrose; group III was fed regular mouse chow ad lib for five months. Liver and heart tissues were fixed in 2.5% cacodylate buffered glutaraldehyde, post-fixed in 2% osmium tetroxide and embedded in Epon-araldite.

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