An update on the role of sex hormones in the function of the cardiorenal mitochondria.

Multiple studies have highlighted the crucial role of mitochondrial bioenergetics in understanding the progression of cardiorenal diseases, revealing new potential treatment targets related to mitochondrial metabolism. There are well-established sexual dimorphisms in cardiac and renal physiology, with premenopausal females being generally protected from pathology compared with males. The mechanisms of this protection remain to be fully elucidated, however, they clearly depend, at least in part, on sex hormones.

Mid-late gestation leptin infusion induces placental mitochondrial and endoplasmic reticulum unfolded protein responses in a mouse model of preeclampsia.

Introduction: Preeclamptic patients, both lean and obese, present with elevated leptin levels which are associated with the development of maternal endothelial dysfunction and adverse fetal outcomes, such as growth restriction, leading to low birth weight. Recent studies in pregnant mice demonstrate that mid-late gestation leptin infusion induces clinical characteristics of preeclampsia, including elevated maternal blood pressure, maternal endothelial dysfunction and fetal growth restriction. However, whether leptin triggers placental stress responses that contribute to adverse fetal outcomes as in preeclampsia is unknown.

Revisiting sex as a biological variable in hypertension research.

Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure.

Optimizing renal transporter immunodetection: consequences of freeze-thaw during sample preparation.

Renal transporters (cotransporters, channels, and claudins) mediate homeostasis of fluids and electrolytes and are targets of hormonal and therapeutic regulators. Assessing renal transporter abundance with antibody probes by immunoblotting is an essential tool for mechanistic studies. Although journals require authors to demonstrate antibody specificity, there are no consensus guidelines for kidney sample preparation leading to lab-to-lab variability in immunoblot results.

Implications of pregnancy on cardiometabolic disease risk: preeclampsia and gestational diabetes.

Cardiometabolic disorders, such as obesity, insulin resistance, and hypertension, prior to and within pregnancy are increasing in prevalence worldwide. Pregnancy-associated cardiometabolic disease poses a great risk to the short- and long-term well-being of the mother and offspring. Hypertensive pregnancy, notably preeclampsia, as well as gestational diabetes are the major diseases of pregnancy growing in prevalence as a result of growing cardiometabolic disease prevalence.

Both endothelial mineralocorticoid receptor expression and hyperleptinemia are required for clinical characteristics of placental ischemia in mice.

One of the initiating events in preeclampsia (PE) is placental ischemia. Rodent models of placental ischemia do not present with vascular endothelial dysfunction, a hallmark of PE. We previously demonstrated a role for leptin in endothelial dysfunction in pregnancy in the absence of placental ischemia.

Physiology of Pregnancy-Related Acute Kidney Injury.

Renal function increases in pregnancy due to the significant hemodynamic demands of plasma volume expansion and the growing feto-placental unit. Therefore, compromised renal function increases the risk for adverse outcomes for pregnant women and their offspring. Acute kidney injury (AKI), or sudden loss of kidney function, is a significant event that requires aggressive clinical management.

Mechanisms of leptin-induced endothelial dysfunction.

Purpose Of Review: Endothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific.

Generation and Comparative Analysis of an Mouse with Preferential Activity in Vascular Smooth Muscle Cells.

All current smooth muscle cell (SMC) mice similarly recombine floxed alleles in vascular and visceral SMCs. Here, we present an knock-in mouse and compare its activity with a mouse. Both drivers demonstrate equivalent recombination in vascular SMCs.

Circulating cell-free micro-RNA as biomarkers: from myocardial infarction to hypertension.

MicroRNA (miRNA) are small, single strand non-coding RNA molecules involved in the post-transcriptional regulation of target genes. Since their discovery in 1993, over 2000 miRNAs have been identified in humans and there is growing interest in both the diagnostic and therapeutic potential of miRNA. The identification of biomarkers for human disease progression remains an active area of research, and there is a growing number of miRNA and miRNA combinations that have been linked to the development and progression of numerous cardiovascular diseases, including hypertension.

Salt Sensitivity of Blood Pressure in Women.

Several clinical and large population studies indicate that women are more salt-sensitive than men, yet the precise mechanisms by which the sexually dimorphic onset manifests remains incompletely understood. Here, we evaluate recent epidemiological data and highlight current knowledge from studies investigating sex-specific mechanisms of salt-sensitive blood pressure (SSBP). Emerging evidence indicates that women of all ethnicities are more salt-sensitive than men, at all ages both premenopausal and postmenopausal.

Endothelial leptin receptor is dispensable for leptin-induced sympatho-activation and hypertension in male mice.

Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes arteries via endothelial (EC) leptin receptor (LepR)-mediated increases in nitric oxide (NO) bioavailability. Herein, we investigated whether leptin-mediated increases in NO bioavailability represent a buffering mechanism against leptin-induced sympatho-activation.

Midgestation Leptin Infusion Induces Characteristics of Clinical Preeclampsia in Mice, Which Is Ablated by Endothelial Mineralocorticoid Receptor Deletion.

Background: Patients with preeclampsia demonstrate increases in placental leptin production in midgestation, and an associated increase in late gestation plasma leptin levels. The consequences of mid-late gestation increases in leptin production in pregnancy is unknown. Our previous work indicates that leptin infusion induces endothelial dysfunction in nonpregnant female mice via leptin-mediated aldosterone production and endothelial mineralocorticoid receptor (ECMR) activation, which is ablated by ECMR deletion.

CXCR4-CCR7 Heterodimerization Is a Driver of Breast Cancer Progression.

Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to the acquisition of the pro-metastatic properties remain poorly understood. We demonstrate here that the CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signalling responses in invasive breast cancer cell lines as well as primary mammary human tumour cells.

Obesity-associated cardiovascular risk in women: hypertension and heart failure.

The pathogenesis of obesity-associated cardiovascular diseases begins long prior to the presentation of a cardiovascular event. In both men and women, cardiovascular events, and their associated hospitalizations and mortality, are often clinically predisposed by the presentation of a chronic cardiovascular risk factor. Obesity increases the risk of cardiovascular diseases in both sexes, however, the clinical prevalence of obesity, as well as its contribution to crucial cardiovascular risk factors is dependent on sex.

Selective deletion of endothelial mineralocorticoid receptor protects from vascular dysfunction in sodium-restricted female mice.

Background: Recent evidence by our laboratory demonstrates that women and female mice endogenously express higher endothelial mineralocorticoid receptor (ECMR) than males. Mounting clinical evidence also indicates that aldosterone production is higher in pathological conditions in females compared to males. However, the role for increased activation of ECMR by aldosterone in the absence of a comorbid condition is yet to be explored.

Dietary sodium restriction sex specifically impairs endothelial function via mineralocorticoid receptor-dependent reduction in NO bioavailability in Balb/C mice.

Recent findings from our group demonstrated that females exhibit higher endothelial mineralocorticoid receptor (MR) expression than males, which predisposes them to aldosterone-mediated endothelial dysfunction in the context of metabolic disorders. However, whether the endothelium of female mice presents a higher propensity to MR-mediated dysfunction than that of males in the absence of comorbidities remains unknown. We therefore sought to investigate whether increasing aldosterone production endogenously with sodium restriction impairs endothelial function in otherwise healthy female mice.

Female Sex, a Major Risk Factor for Salt-Sensitive Hypertension.

Purpose Of Review: High dietary salt is a significant contributor to essential hypertension in clinical populations. However, although clinical studies indicate a higher prevalence of salt sensitivity in women over men, knowledge of salt-sensitive mechanisms is largely restricted to males, and female-specific mechanisms are presently being elucidated.

Recent Findings: Male-specific mechanisms of salt-sensitive hypertension are well published and predominantly appear to involve dysfunctional renal physiology.

High Resolution Melt Assays to Detect and Identify , , , and Bacteria.

Over one hundred bacterial species have been determined to comprise the human microbiota in a healthy individual. Bacteria including , , , and are found inside of the human body and and are also found on the skin. These bacteria can act as human pathogens upon ingestion of contaminated food or water, if they enter an open wound, or antibiotics, and environment or stress can alter the microbiome.

17-Hydroxyprogesterone caproate improves T cells and NK cells in response to placental ischemia; new mechanisms of action for an old drug.

Preeclampsia (PE) is new onset hypertension during pregnancy associated with increased uterine artery resistance (UARI) and an imbalance among CD4 + T lymphocytes and natural killer (NK) cells. We have shown an important role for 17-hydroxyprogesterone caproate (17-OHPC) to improve hypertension and fetal demise in the RUPP rat model of PE. However we have not examined a role for 17-OHPC to improve NK cells and CD4TH2 cells as possible mechanisms for improved fetal weight and hypertension.

Leptin Restores Endothelial Function via Endothelial PPARγ-Nox1-Mediated Mechanisms in a Mouse Model of Congenital Generalized Lipodystrophy.

Leptin is the current treatment for metabolic disorders associated with acquired and congenital generalized lipodystrophy (CGL). Although excess leptin levels have been associated with vascular inflammation and cardiovascular disease in the context of obesity, the effects of chronic leptin treatment on vascular function remain unknown in CGL. Here, we hypothesized that leptin treatment will improve endothelial function via direct vascular mechanisms.

Mineralocorticoid Receptor and Endothelial Dysfunction in Hypertension.

Purpose Of Review: To review the latest reports of the contributions of the endothelial mineralocorticoid receptor to endothelial dysfunction and hypertension to begin to determine the clinical potential for this pathway for hypertension treatment.

Recent Findings: Endothelial mineralocorticoid receptor expression is sex-specifically increased in female mice and humans compared with males. Moreover, the expression of endothelial mineralocorticoid receptors is increased by endothelial progesterone receptor activation and naturally occurring fluctuations in progesterone levels (estrous, pregnancy) predict endothelial mineralocorticoid receptor expression levels in female mice.