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

The lining of blood vessels is constantly exposed to mechanical forces exerted by blood flow against the endothelium. Endothelial cells detect these tangential forces (i.e., shear stress), initiating a host of intracellular signaling cascades that regulate vascular physiology. Thus, vascular health is tethered to the endothelial cells' capacity to transduce shear stress. Indeed, the mechanotransduction of shear stress underlies a variety of cardiovascular benefits, including some of those associated with increased physical activity. However, endothelial mechanotransduction is impaired in aging and disease states such as obesity and type 2 diabetes, precipitating the development of vascular disease. Understanding endothelial mechanotransduction of shear stress, and the molecular and cellular mechanisms by which this process becomes defective, is critical for the identification and development of novel therapeutic targets against cardiovascular disease. In this review, we detail the primary mechanosensitive structures that have been implicated in detecting shear stress, including junctional proteins such as platelet endothelial cell adhesion molecule-1 (PECAM-1), the extracellular glycocalyx and its components, and ion channels such as piezo1. We delineate which molecules are truly mechanosensitive and which may simply be indispensable for the downstream transmission of force. Furthermore, we discuss how these mechanosensors interact with other cellular structures, such as the cytoskeleton and membrane lipid rafts, which are implicated in translating shear forces to biochemical signals. Based on findings to date, we also seek to integrate these cellular and molecular mechanisms with a view of deciphering endothelial mechanotransduction of shear stress, a tenet of vascular physiology.

The physiological consequences of environment-induced heat stress (EIHS), caused by prolonged exposure to excess heat and humidity, are largely unknown. The purpose of this investigation was to determine the extent to which EIHS alters cardiac health. We hypothesized that 24 h of EIHS would cause cardiac injury and cellular dysfunction in a murine EIHS model. To test this hypothesis, 7-wk-old female mice were housed under thermoneutral (TN) conditions (n = 12; 31.2 ± 1.01°C, 35 ± 0.7% humidity) or EIHS conditions (n = 14; 37.6 ± 0.01°C, 42.0 ± 0.06% humidity) for 24 h. Environment-induced heat stress increased rectal temperature by 2.1°C (P < 0.01) and increased subcutaneous temperature by 1.8°C (P < 0.01). Body weight was decreased by 10% (P = 0.03), heart weight/body weight was increased by 26% (P < 0.01), and tissue water content was increased by 11% (P < 0.05) in EIHS compared with TN. In comparison with TN, EIHS increased protein abundance of heat shock protein (HSP) 27 by 84% (P = 0.01); however, HSPs 90, 60, 70, and phosphorylated HSP 27 were similar between groups. Histological inspection of the heart revealed that EIHS animals had increased myocyte vacuolation in the left ventricle (P = 0.01), right ventricle (P < 0.01), and septum (P = 0.01) compared with TN animals. Biochemical indices are suggestive of mitochondrial remodeling, increased autophagic flux, and robust activation of endoplasmic reticulum stress in hearts from EIHS mice compared with TN mice. These data demonstrate that 1 day of EIHS is sufficient to induce myocardial injury and biochemical dysregulation.NEW & NOTEWORTHY The consequences of prolonged environment-induced heat stress (EIHS) on heart health are largely unknown. We discovered that a 24-h exposure to environmental conditions sufficient to cause EIHS resulted in cardiac edema and histopathologic changes in the right and left ventricles. Furthermore, among other biochemical changes, EIHS increased autophagic flux and caused endoplasmic reticulum stress. These data raise the possibility that thermic injury, even when insufficient to cause heat stroke, can damage the myocardium.

High-altitude (HA) hypoxia lowers uterine artery (UtA) blood flow during pregnancy and birth weight. Adenosine monophosphate kinase (AMPK) activation has selective, uteroplacental vasodilator effects that lessen hypoxia-associated birth weight reductions. In this study, we determined the relationship between AMPK-pathway gene expression and metabolites in the maternal circulation during HA pregnancy as well as with the maintenance of UtA blood flow and birth weight at HA. Residents at HA (2,793 m) versus low altitude (LA; 1,640 m) had smaller UtA diameters at weeks 20 and 34, lower UtA blood flow at week 20, and lower birth weight babies. At week 34, women residing at HA versus women residing at LA had decreased expression of upstream and downstream AMPK-pathway genes. Expression of the α₁-AMPK catalytic subunit, PRKAA1, correlated positively with UtA diameter and blood flow at weeks 20 (HA) and 34 (LA). Downstream AMPK-pathway gene expression positively correlated with week 20 fetal biometry at both altitudes and with UtA diameter and birth weight at LA. Reduced gene expression of AMPK activators and downstream targets in women residing at HA versus women residing at LA, together with positive correlations between PRKAA1 gene expression, UtA diameter, and blood flow suggest that greater sensitivity to AMPK activation at midgestation at HA may help offset later depressant effects of hypoxia on fetal growth.NEW & NOTEWORTHY Fetal growth restriction (FGR) is increased and uterine artery (UtA) blood flow is lower at high altitudes (HA) but not all HA pregnancies have FGR. Here we show that greater UtA diameter and blood flow at week 20 are positively correlated with higher expression of the gene encoding the α₁-catalytic subunit of AMP protein kinase, PRKAA1, suggesting that increased AMPK activation may help to prevent the detrimental effects of chronic hypoxia on fetal growth.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10^-10-10^-1 M) and insulin (10^-8-10^-4 M) in control sites and sites treated with 15 mM l-NAME [N^G-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Aortic perivascular adipose tissue (aPVAT) density is associated with age-related aortic stiffness in humans and therefore, may contribute to cardiovascular dysfunction. A lower subendocardial viability ratio (SEVR), an estimate of myocardial perfusion, indicates greater cardiovascular disease (CVD) risk and is associated with aortic stiffness in clinical populations. However, the influence of aortic stiffness on the relation between aPVAT density and SEVR/cardiovascular (CV) hemodynamics in apparently healthy adults is unknown. We hypothesize that greater aPVAT density will be associated with lower SEVR and higher CV hemodynamics independent of aortic stiffness. Fourteen (6 males/8 females; mean age, 55.4 ± 5.6 yr; body mass index, 25.5 ± 0.6 kg/m²) adults completed resting measures of myocardial perfusion (SEVR), CV hemodynamics (pulse wave analysis), aortic stiffness [carotid-femoral pulse wave velocity (cfPWV)], and a computed tomography scan to acquire aPVAT and visceral adipose tissue (VAT) density. Greater aPVAT density (i.e., higher density) was associated with lower SEVR (r = -0.78, P < 0.001) and a higher systolic pressure time integral (r = 0.49, P = 0.03), forward pulse height (r = 0.49, P = 0.03), reflected pulse height (r = 0.55, P = 0.02), ejection duration (r = 0.56, P = 0.02), and augmentation pressure (r = 0.69, P = 0.003), but not with the diastolic pressure time integral (r = -0.22, P = 0.22). VAT density was not associated with SEVR or any CV hemodynamic endpoints (all, P > 0.05). Furthermore, the relation between aPVAT density and SEVR remained after adjusting for aortic stiffness (r = -0.66, P = 0.01) but not age (r = -0.24, P > 0.05). These data provide initial evidence for aPVAT as a novel yet understudied local fat depot contributing to lower myocardial perfusion in apparently healthy adults with aging.NEW & NOTEWORTHY Aortic perivascular adipose tissue (aPVAT) density is associated with aging and aortic stiffness in humans and, therefore, may contribute to lower myocardial perfusion. We demonstrate that greater aPVAT, but not visceral adipose tissue density is associated with lower myocardial perfusion and augmentation pressure independent of aortic stiffness, but not independent of age. These data provide novel evidence for aPVAT as a potential therapeutic target to improve myocardial perfusion and cardiovascular function in humans with aging.

T-cell accumulation within the aorta promotes endothelial dysfunction and the genesis of cardiovascular disease, including hypertension and atherosclerosis. Viral infection during pregnancy is also known to mediate marked acute endothelial dysfunction, but it is not clear whether T cells are recruited to the aorta and whether the dysfunction persists postpartum. Here, we demonstrate that influenza A virus (IAV) infection during pregnancy in a murine model resulted in endothelial dysfunction of the aorta, which persisted for up to 60 days postinfection and was associated with higher levels of IFN-γ mRNA expression within the tissue. In the absence of infection, low numbers of naïve CD4⁺ and CD8⁺ T cells, central memory T cells, and effector memory T cells were observed in the aorta. However, with IAV infection, these T-cell subsets were significantly increased with a notable accumulation of IAV-specific CD8⁺ effector memory T cells. Critically, this increase was maintained out to at least 60 days. In contrast, IAV infection in nonpregnant female mice resulted in modest endothelial dysfunction with no accumulation of T cells within the aorta. These data, therefore, demonstrate that the aorta is a site of T-cell recruitment and retention after IAV infection during pregnancy. Although IAV-specific memory T cells could theoretically confer protection against future influenza infection, nonspecific memory T-cell activation and IFN-γ production in the aorta could also contribute to future endothelial dysfunction and cardiovascular disease.NEW & NOTEWORTHY Pregnancy is a risk factor for cardiovascular complications to influenza A virus (IAV) infection. We demonstrate that gestational IAV infection caused endothelial dysfunction of the maternal aorta, which persisted for 60 days postinfection in mice. Various T cells accumulated within the aorta at 60 days because of the infection, and this was associated with elevated levels of the proinflammatory cytokine, IFN-γ. Our study demonstrates a novel "long influenza" cardiovascular phenotype in female mice.

Exaggerated blood pressure (BP) responses during exercise are independently associated with future development of hypertension. Partial sleep deprivation (PSD) can increase 24-h ambulatory BP, but the effects on exercise BP are unclear. We hypothesized that acute PSD would augment the BP response to constant load cycling exercise and a 20-min time trial. Twenty-two healthy adults (22 ± 3 yr old; 13 males; V̇o_2peak, 43.6 ± 8.2 mL·kg^-1·min^-1) completed a randomized crossover trial in which they either slept normally (normal sleep-wake schedule for each participant) or sleep was partially deprived (early awakening, 40% of normal sleep duration). Each participant completed a 12-min warm-up consisting of two 6-min steps (step 1, 62 ± 25 W; step 2, 137 ± 60 W) followed by a 20-min time trial on a cycle ergometer. PSD did not alter power output during the 20-min time trial [(control vs. PSD) 170 ± 68 vs. 168 ± 68 W, P = 0.65]. Systolic BP did not differ during step 1 of the warm-up (141 ± 15 vs. 137 ± 12 mmHg, P = 0.39) but was lower following PSD during step 2 (165 ± 21 vs. 159 ± 22 mmHg, P = 0.004) and the 20-min time trial (171 ± 20 vs. 164 ± 23 mmHg, P < 0.001). These results were maintained when peak oxygen uptake (V̇o_2peak) was included as a covariate. Systolic BP responses were modulated by sex (time × visit × sex interaction P = 0.03), with attenuated systolic BP during the warm-up and the 20-min time trial in males but not in females. In contrast to our hypothesis, acute PSD attenuates systolic BP responses during constant load and 20-min time trial cycling exercise; however, these observations appear to be primarily driven by changes in males.NEW & NOTEWORTHY A single night of partial sleep deprivation (PSD) can increase ambulatory blood pressure (BP) the following day. Despite this phenomenon, the present study found that acute PSD attenuates systolic BP responses to both constant load cycling and a 20-min cycling time trial in young healthy adults. Interestingly, the attenuated systolic BP responses following PSD appeared to be modulated by sex such that attenuations were observed in males but not in females.

Thoracic aortic aneurysm (TAA) is associated with Marfan syndrome (MFS), a connective tissue disorder caused by mutations in fibrillin-1. Sexual dimorphism has been recorded for TAA outcomes in MFS, but detailed studies on the differences in TAA progression in males and females and their relationships to outcomes have not been performed. The aims of this study were to determine sex differences in the diameter dilatation, mechanical properties, and extracellular matrix (ECM) remodeling over time in a severe mouse model (Fbn1^mgR/mgR = MU) of MFS-associated TAA that has a shortened life span. Male and female MU and wildtype (WT) mice were used at 1-4 mo of age. Blood pressure and in vivo diameters of the ascending thoracic aorta were recorded using a tail-cuff system and ultrasound imaging, respectively. Ex vivo mechanics and ECM remodeling of the aorta were characterized using a biaxial test system and multiphoton imaging, respectively. We showed that mechanical properties, such as structural and material stiffness, and ECM remodeling, such as elastic and collagen fiber content, correlated with diameter dilatation during TAA progression. Male MU mice had accelerated rates of diameter dilatation, stiffening, and ECM remodeling compared with female MU mice which may have contributed to their decreased life span. The correlation of mechanical properties and ECM remodeling with diameter dilatation suggests that they may be useful biomarkers for TAA progression. The differences in diameter dilatation and life spans in male and female MU mice indicate that sex is an important consideration for managing thoracic aortic aneurysm in MFS. NEW & NOTEWORTHY Using a mouse model (Fbn1^mgR/mgR = MU) of severe thoracic aortic aneurysm in Marfan syndrome (MFS), we found that male MU aorta had an accelerated time line and increased amounts of dilatation, stiffening, and extracellular matrix (ECM) remodeling compared with female MU aorta that may have contributed to an increased risk of fatigue failure with cyclic loading over time and a reduced life span. We suggest that aortic stiffness may provide useful information for clinical management of aneurysms in MFS.