American journal of physiology. Heart and circulatory physiology最新文献

The capacity of the endothelium to release tissue-type plasminogen activator (t-PA) is markedly impaired in adults with obesity, underlying their increased thrombotic risk. Circulating endothelial cell-derived microvesicles (EMVs) are systemic modulators of vascular health and disease, and are elevated with obesity. The experimental aim of this study was to determine whether circulating EMVs are associated with obesity-related endothelial fibrinolytic dysfunction. Twenty-eight sedentary, midlife and older adults (45-71 yr) were studied: 14 normal-weight (7 M/7 F; age: 55 ± 4 yr; body mass index: 23.1 ± 1.6 kg/m²) adults and 14 adults with obesity (7 M/7 F; 57 ± 8 yr; 31.9 ± 2.9 kg/m²). EMV identification (CD144⁺) and concentration in peripheral blood were determined by flow cytometry. Endothelial release of t-PA was determined, in vivo, in response to intrabrachial infusions of bradykinin (BK: 125-500 ng/min) and sodium nitroprusside (SNP: 2.0-8.0 µg/min). Circulating EMV levels were ∼170% higher (P < 0.001) in adults with obesity (183 ± 58 EMV/µL) compared with normal-weight (68 ± 12 EMV/µL) adults. Endothelial t-PA release in response to BK was significantly lower (∼30%) in the adults with obesity (from 0.7 ± 3.6 to 35.9 ± 15.1 ng/100 mL tissue/min) versus normal-weight adults (-0.5 ± 2.3 to 68.4 ± 21.1 ng/100 mL tissue/min). Consequently, total t-PA release (area under the BK curve) was lower (∼35%; P = 0.007) in the adults with obesity (205 ± 118 ng/100 mL tissue vs. 325 ± 97 ng/100 mL tissue). Circulating EMVs were significantly and inversely associated with both peak t-PA release (r = -0.67; P = 0.0001) and total t-PA release to BK (r = -0.53; P = 0.004). In summary, obesity-related increase in circulating EMVs is associated with diminished endothelial t-PA release. Circulating EMVs may serve as a biomarker of fibrinolytic dysfunction in adults with obesity.NEW & NOTEWORTHY Obesity is associated with profound impairment in the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA), the primary mechanism underlying endogenous thrombolysis. Circulating endothelial cell-derived extracellular vesicles (EMVs) have been linked to endothelial dysfunction. This study demonstrates that circulating EMVs are elevated in adults with obesity and are associated with reduced endothelial t-PA release. Circulating EMVs represent a novel systemic biomarker of obesity-related endothelial fibrinolytic dysfunction and, in turn, thrombotic risk.

Exercise training has been shown to reverse cardiac dysfunction in patients and animal models of coronary artery disease; however, the underlying mechanisms have not been fully elucidated. Transmembrane integrins that connect the extracellular matrix (ECM) and intracellular cytoskeleton are important for mechanotransduction in cardiomyocytes. We tested the hypothesis that exercise training would increase cardiac contractile function by modulating the adhesion force between integrins and ECM proteins and subsequent cell signaling and stiffness in myocytes from ischemic porcine hearts. Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of adult Yucatan pigs. Animals subsequently completed either a sedentary or endurance exercise (treadmill run 5 days/wk for 14 wk) protocol, after which myocardium was isolated from nonoccluded and collateral-dependent regions. The collateral-dependent myocardial region exhibited increased fibrosis, inflammatory cytokines, and collagen I and III levels, which were ameliorated with exercise training. Exercise also increased fibronectin and β1 integrin and decreased β3 integrin levels in collateral-dependent myocardium compared with that of sedentary pigs. Atomic force microscopy revealed that an increase in fibronectin-integrin adhesion force was mediated by α₅β₁ and α_vβ₃ integrins in cardiac myocytes of exercise-trained pigs. Exercise training increased mechanical stiffness in cardiomyocytes compared with that in sedentary swine. Fibronectin- and exercise-induced force generation in trabeculae from collateral-dependent myocardium was each decreased by focal adhesion kinase (FAK) inhibition. These data demonstrate that exercise training increases force generation in cardiomyocytes by attenuating inflammation and by promoting fibronectin-mediated FAK activation, suggesting potential targeting of this mechanotransduction pathway for therapeutic development.NEW & NOTEWORTHY Exercise produces cardioprotective effects and reverses cardiac dysfunction, but underlying cellular and molecular mechanisms are not fully identified. This study revealed that endurance exercise increased fibronectin expression in the myocardium of ischemic swine hearts and enhanced myocyte adhesion with α₅β₁ integrin, cell stiffness, and force generation, which was blunted by focal adhesion kinase inhibition. Thus, endurance exercise reverses cardiac dysfunction by promoting fibronectin interactions with integrins supporting this mechanotransduction pathway as a potential therapeutic target.

Obesity in pregnant women increases offspring cardiovascular risk and causes fetal cardiac dysfunction. The underpinning mechanisms remain unclear. We hypothesized that circulating factors in serum from fetuses of women with obesity induce pathological cardiomyocyte hypertrophy. Pregnant women with obesity or healthy weight were recruited at term and provided umbilical cord serum and placentas, which were used for isolation of primary trophoblast cells. Primary cardiomyocytes were isolated from neonatal rats. Compared with cord serum from healthy weight women, cord serum from women with obesity upregulated cardiomyocyte mRNA expression of atrial natriuretic factor (Anf) and brain natriuretic peptide (Bnp) and increased the ratio of β-to α-myosin heavy chain expression (Myh7:Myh6), when it was supplemented into the culture medium. This effect was prevented by treating the cord serum with heat-freeze cycling and DNase or RNase digestion. Separately, conditioned medium from trophoblast cells from women with obesity increased cardiomyocyte Anf expression without altering Bnp or Myh7:Myh6. MicroRNAs miR-142 and miR-17, which are associated with cardiac function, were increased in abundance in extracellular vesicles isolated from cord serum from women with obesity. However, miR-142-3p, miR-142-5p, and miR-17-5p did not increase Anf, Bnp, or Myh7:Myh6 expression when they were transfected into cardiomyocytes. Neither cord serum nor the upregulated microRNAs from women with obesity altered cardiomyocyte size. The results show that human fetal circulating and placenta-derived factors induce gene expression hallmarks of pathological hypertrophy in cardiomyocytes and may mediate cardiac dysfunction in children of women with obesity.NEW & NOTEWORTHY Obesity in pregnant women increases risk for heart problems in their children. This study treated heart cells growing in a dish with blood plasma from the umbilical cords of newborn babies. Plasma from babies of women with obesity activated genes linked to heart failure. This means we could design treatments targeting plasma molecules, like microRNAs, or the way the placenta releases them. This could improve children's heart health if the mother has obesity.

Fetal growth restriction (FGR) secondary to placental insufficiency often leads to morbidity and mortality in the perinatal period. Fetal adaptations such as "brain sparing" blood flow redistribution offer some protection, but predicting whether a fetus in this state will survive is challenging. The goal of this research was to identify vascular responses predictive of stillbirth or hypoxia based on serial Doppler ultrasound measurement in a mouse model of FGR. We performed serial Doppler ultrasound observations of fetal blood flow redistribution in a murine model of FGR, where prolongation of pregnancy was induced pharmacologically with progesterone in 56 CD-1 mice. Observations were made at E18.5 (physiologic term), E19.5 (term +1), and E20.5 (term +2). Flow velocity waveforms were obtained from the middle cerebral artery (MCA), ductus arteriosus (DA), main pulmonary artery (MPA), ductus venosus (DV), umbilical artery (UA), and umbilical vein (UV). Following euthanasia, pimonidazole immunohistochemistry quantified tissue hypoxia. Among 56 pregnancies, the strongest predictor of stillbirth was low DA peak systolic velocity at E19.5 (<217 mm/s, P = 0.021, R² = 0.52). Among survivors, cerebral hypoxia was predicted by elevated MCA peak systolic (>26.6 mm/s, P = 0.022, R² = 0.59) and end-diastolic velocity (>10.1 mm/s, P = 0.043, R² = 0.53, whereas high MPA flow (>0.73 mL/min, P = 0.029, R² = 0.51) predicted hepatic hypoxia. Overall, fetuses with a weaker pulmonary blood flow redistribution response were found to have worse outcomes, despite cerebral vasodilation. This minimally invasive murine model offers valuable insights into this pathophysiology of FGR-related stillbirth and highlights the prognostic potential of assessing fetal brain flow and pulmonary perfusion in tandem during sonographic surveillance of high-risk pregnancies.NEW & NOTEWORTHY Fetal growth restriction, often caused by placental disease, is an important cause of fetal injury and stillbirth. Understanding how the fetus adapts under these conditions is key to predicting survival. Here we report physiological adaptations in a mouse of model of fetal growth restriction that predict the risk of stillbirth.

The global rise in obesity parallels the increasing rates of hypertension and cardiovascular disease (CVD). These trends, and recent clinical and experimental data, have revealed that obesity abolishes the protection from CVD typically conferred by female sex, predisposing young, premenopausal women to vascular dysfunction and hypertension. Findings from our group demonstrated that, in females, obesity induces hypertension via activation of the leptin-aldosterone-mineralocorticoid receptor (MR) axis. However, the origin of this sex-specific mechanism remains unknown. Based on the known effects of estrogen on blood pressure (BP) and vascular function, we tested the contribution of sex hormones. Sham and ovariectomy (OVX) surgeries were conducted in obese female agouti yellow mice to preserve or deplete female sex hormones, respectively. OVX did not significantly alter blood pressure (BP) nor autonomic control of BP or adrenal aldosterone synthase (CYP11B2) expression; however, it impaired endothelial relaxation with no further alterations to vascular function. Chronic leptin receptor blockade decreased BP in both sham and OVX mice and restored endothelium-dependent relaxation, suggesting a lack of contribution of female sex hormones to the mechanism of hypertension. Stimulation of HAC15 and human primary adrenocortical cells with female and male sex steroid hormones did not alter CYP11B2 expression. Furthermore, quantification of CYP11B2 expression in discarded human adrenal glands revealed increases with obesity in women in comparison to men and no alterations with menopause in obese hypertensive women. Collectively, these findings support that female sex hormones do not regulate aldosterone production nor do they drive the sex-specific mechanism underlying obesity-associated hypertension.NEW & NOTEWORTHY Obesity induces hypertension in females through the leptin-aldosterone-mineralocorticoid axis; however, the origin of this sex-specific mechanism remains unknown. Utilizing obese female mice, ovariectomy did not significantly impair blood pressure (BP), vascular function, or aldosterone synthase, whereas leptin receptor blockade lowered BP and restored vascular reactivity. In human cells and tissues, sex hormones did not alter aldosterone synthase expression. These data indicate that sex hormones do not drive the sex difference in the mechanism of obesity-associated hypertension.