Corticosteroid hormones play an important role in the control of vascular smooth muscle tone by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. Increased cortisol response has been associated with an increase in arterial contractile sensitivity to norepinephrine and vascular resistance. Glucocorticoids regulate vascular reactivity by acting on both endothelial and vascular smooth muscle cells. Both glucocorticoid receptor protein and mRNA have been identified in endothelial and vascular smooth muscle cells. In endothelial cells, glucocorticoids suppress the production of vasodilators, such as prostacyclin and nitric oxide. In vascular smooth muscle cells, glucocorticoids enhance agonist-mediated pharmacomechanical coupling at multiple levels. The effect of glucocorticoids on vascular reactivity is regulated by 11 β-hydr oxysteroid de hydrogenase (11β-HSD ). The presence of 11β-HSD in many tissue s suggests that it modulates the access of corticosteroids to the irreceptors at both renal and extra-renal sites. The two 11β-HSD isozyme scatalyze the inte rconversion of cortisol and cortisone . Type 1 11β-HSD has bidirec tiona l activity, while the type 2 mainly conver ts cortisol into cor tisone, the biologically inactive form. Both type 1 and type 2 11β-HSD have been found in vascular e ndothelial and smooth muscle c ells, suggesting that a bnormal 11β- HSD expression may play a pathoge nicrole in the common forms of hypertension. In this a rticle, we review possible mechanisms involved in the glucocorticoid-mediated potentiation of vascular reactivity, its regulation by 11β-HSD , and their physiological and pathophysiologica l significance.

Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although “normal” hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the hearts development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predisposes the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation.

Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual’s genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine “genomic plasticity,” i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual’s physiology and developmental programming of health and disease later in life are discussed.

Background: Ischemic heart disease remains a leading cause of death worldwide. In this study, we test the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion (IR) injury by controlling mitochondrial bioenergetics and reactive oxygen species (ROS) flux. Methods: Myocardial infarction in an acute setting of IR was examined via comparing loss vs. gain of function experiments in microRNA-210-deficient and wild type mice. Cardiac function was evaluated by echocardiography. Myocardial mitochondria bioenergetics was examined using a Seahorse XF24 Analyzer. Results: MicroRNA-210 deficiency significantly exaggerated cardiac dysfunction up to 6 weeks after myocardial IR in male, but not female, mice. Intravenous injection of microRNA-210 mimic blocked the effect and recovered the increased myocardial IR injury and cardiac dysfunction. Analysis of mitochondrial metabolism revealed that microRNA-210 inhibited mitochondrial oxygen consumption, increased glycolytic activity, and reduced mitochondrial ROS flux in the heart during IR injury. Consistently, inhibition of mitochondrial ROS with MitoQ reversed the effect of microRNA-210 deficiency. Mechanistically, we showed that mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is a novel target of microRNA-210 in the heart, and loss-of-function and gain-of-function experiments revealed that GPD2 played a key role in the microRNA-210-mediated effect on mitochondrial metabolism and ROS flux in the setting of heart IR injury. Knockdown of GPD2 negated microRNA-210 deficiency-induced increases in mitochondrial ROS production and myocardial infarction, and improved left ventricular fractional shortening and ejection fraction after the IR treatment. Conclusions: MicroRNA-210 targeting GPD2 controls mitochondrial bioenergetics and ROS flux and improves cardiac function in a murine model of myocardial infarction in the setting of IR injury. The findings suggest new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.