Background-The glucagon-like peptide 1 receptor (GLP-1R) is believed to mediate glucoregulatory and cardiovascular effects of the incretin hormone GLP-1(7-36) (GLP-1), which is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to GLP-1(9-36), a truncated metabolite generally thought to be inactive. Novel drugs for the treatment of diabetes include analogues of GLP-1 and inhibitors of DPP-4; however, the cardiovascular effects of distinct GLP-1 peptides have received limited attention. Methods and Results-Here, we show that endothelium and cardiac and vascular myocytes express a functional GLP-1R as GLP-1 administration increased glucose uptake, cAMP and cGMP release, left ventricular developed pressure, and coronary flow in isolated mouse hearts. GLP-1 also increased functional recovery and cardiomyocyte viability after ischemiareperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r Ϫ/Ϫ mice. Furthermore, GLP-1(9-36) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release, vasodilatation, and coronary flow in wild-type and Glp1r Ϫ/Ϫ mice, with modest effects on glucose uptake. Studies using a DPP-4 -resistant GLP-1R agonist and inhibitors of DPP-4 and nitric oxide synthase showed that the effects of GLP-1(7-36) were partly mediated by GLP-1(9-36) through a nitric oxide synthase-requiring mechanism that is independent of the known GLP-1R. Conclusions-These data describe cardioprotective actions of GLP-1(7-36) mediated through the known GLP-1R and novel cardiac and vascular actions of GLP-1(7-36) and its metabolite GLP-1(9-36) independent of the known GLP-1R. Our data suggest that the extent to which GLP-1 is metabolized to GLP-1(9-36) may have functional implications in the cardiovascular system.
Changes in diaphragm thickness are common during mechanical ventilation and may be associated with diaphragmatic weakness. Titrating ventilatory support to maintain normal levels of inspiratory effort may prevent changes in diaphragm configuration associated with mechanical ventilation.
Connexins have been hypothesized to play an important role in intercellular communication within the vascular wall and may provide a mechanistic explanation for conduction of vasomotor responses. To test this hypothesis, we studied the transmission of vasomotor responses in the intact skeletal muscle microcirculation of connexin40-deficient mice (Cx40(-/-)). Arterioles were locally stimulated with hyperpolarizing dilators (acetylcholine [ACh] as well as bradykinin [Bk]) or depolarizing K(+) solution, and the resulting changes in diameter were measured using a videomicroscopy technique at the site of application and up to 1.32 mm upstream. Arterial pressure was elevated 25% in Cx40(-/-) mice (94+/-5 versus 75+/-4 mm Hg). Vessels selected for study had equivalent basal diameter and vasomotor tone in both genotypes of mice. Vasomotion was present in small arterioles of both genotypes, but its intensity was exaggerated in Cx40(-/-) mice. ACh and Bk induced dilation (33% and 53%, respectively, of maximal response) at the site of application that was of similar magnitude in both genotypes. These dilations were observed to spread upstream within <1 second without significant attenuation in Cx40(+/+) mice. However, spreading was severely attenuated in Cx40(-/-) animals (11+/-4% versus 35+/-7% with ACh and 38+/-5% versus 60+/-7% with Bk in Cx40(-/-) and Cx40(+/+), respectively; P<0.05). In contrast, conducted vasoconstrictions, induced by K(+) solution decreased equally with distance in both genotypes. These results support a significant role for Cx40 in vascular intercellular communication. Our observations indicate that Cx40 is required for normal transmission of endothelium-dependent vasodilator responses and may underlie altered vasomotion patterns.
Gap-junctional communication coordinates the behavior of individual cells in arterioles. Gap junctions are formed by connexins 40 (Cx40), Cx43, Cx37, and Cx45 in the vasculature. Previously, we have shown that lack of Cx40 impairs conduction of dilatory signals along arterioles. Herein, we examined whether hypertension is present in conscious animals and whether this is a direct effect or due to secondary mechanisms. Mean arterial pressure was elevated by 20–25 mmHg in conscious Cx40-deficient mice (Cx40−/−) compared with wild-type controls in both sexes. Differences in heart rate were not observed. Blockade of NO synthase increased pressure equally in both genotypes. Conversely, the angiotensin AT1-receptor antagonist, candesartan, decreased pressure to similar extents in Cx40−/− and wild-type mice. Acetylcholine and sodium nitroprusside (0.05–15 nmol) were equally potent and effective in decreasing pressure and inducing dilatory responses in the microcirculation. However, in contrast to wild type, Cx40−/− arterioles exhibited spontaneous, irregular vasomotion leading temporarily to complete vessel closure. We conclude that loss of Cx40 is associated with hypertension independent of the action of angiotensin II. It is also not related to an altered efficacy of NO or other endothelial dilators. However, the observed irregular vasomotion suggests that peripheral vascular resistance is affected.
The S1P 2 receptor is a member of a family of G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. The receptor is widely expressed and linked to multiple G protein signaling pathways, but its physiological function has remained elusive. Here we have demonstrated that S1P 2 receptor expression is essential for proper functioning of the auditory and vestibular systems. Auditory brainstem response analysis revealed that S1P 2 receptor-null mice were deaf by one month of age. These null mice exhibited multiple inner ear pathologies. However, some of the earliest cellular lesions in the cochlea were found within the stria vascularis, a barrier epithelium containing the primary vasculature of the inner ear. Between 2 and 4 weeks after birth, the basal and marginal epithelial cell barriers and the capillary bed within the stria vascularis of the S1P 2 receptor-null mice showed markedly disturbed structures. JTE013, an S1P 2 receptor-specific antagonist, blocked the S1P-induced vasoconstriction of the spiral modiolar artery, which supplies blood directly to the stria vascularis and protects its capillary bed from high perfusion pressure. Vascular disturbance within the stria vascularis is a potential mechanism that leads to deafness in the S1P 2 receptor-null mice. Sphingosine 1-phosphate (S1P)3 is a sphingolipid metabolite that functions as a signaling ligand through interactions with G protein-coupled S1P receptors. Five high affinity receptors (S1P 1 -S1P 5 ) have been described that trigger distinctive intracellular signaling pathways (1, 2) following binding of the S1P ligand. Three of these receptors, S1P 1 , S1P 2 , and S1P 3 , are widely expressed on cells and tissues, whereas expression of the S1P 4 and S1P 5 receptors are largely confined to cells of the immune and nervous systems. The ligand S1P is produced through the phosphorylation of sphingosine by sphingosine kinases 1 and 2 and can be degraded by S1P-specific enzymes that include phosphatases and a lyase (3). Micromolar levels of the S1P ligand, bound primarily to high density lipoproteins, are found in plasma and may provide a source for tonic signaling. Acute S1P signaling may result from enhanced secretion of S1P from cells, such as platelets and mast cells, upon activation.Genetic deletion of receptors within mice has been an important means of identifying the physiologic roles of S1P receptor signaling. These studies have demonstrated that the signaling pathways are biologically significant and potentially clinically relevant within the vascular (4 -6), immune (7, 8), pulmonary (9), and nervous systems (10).Here we report that S1P 2 receptor expression is essential for proper functioning of the auditory and vestibular systems. S1P 2 receptor-null mice exhibit profound deafness early in life with severe associated pathologic changes within the cochlea. Early cellular defects were found to be in the stria vascularis, a compartment that harbors the main vasculature of the inner ea...
We developed an assay to quantify LDL transcytosis across endothelial cells and discovered an unexpected role for SR-BI. Elucidating the mechanisms of LDL transcytosis may identify novel targets for the prevention or therapy of atherosclerosis.
Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental to survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently in the cellular responses to acute hypoxia, we defined the effects of NOS deficiency in acute anemia. In contrast to endothelial NOS or inducible NOS deficiency, neuronal NOS (nNOS) −/− mice demonstrated increased mortality during anemia. Unlike wild-type (WT) animals, anemia did not increase cardiac output (CO) or reduce systemic vascular resistance (SVR) in nNOS −/− mice. At the cellular level, anemia increased expression of HIF-1α protein and HIF-responsive mRNA levels (EPO, VEGF, GLUT1, PDK1) in the brain of WT, but not nNOS −/− mice, despite comparable reductions in tissue PO 2 . Paradoxically, nNOS −/− mice survived longer during hypoxia, retained the ability to regulate CO and SVR, and increased brain HIF-α protein levels and HIF-responsive mRNA transcripts. Real-time imaging of transgenic animals expressing a reporter HIF-α(ODD)-luciferase chimeric protein confirmed that nNOS was essential for anemia-mediated increases in HIF-α protein stability in vivo. S -nitrosylation effects the functional interaction between HIF and pVHL. We found that anemia led to nNOS-dependent S -nitrosylation of pVHL in vivo and, of interest, led to decreased expression of GSNO reductase. These findings identify nNOS effects on the HIF/pVHL signaling pathway as critically important in the physiological responses to anemia in vivo and provide essential mechanistic insight into the differences between anemia and hypoxia.
Background-NO-induced dilations in resistance arteries (RAs) are not associated with decreases in vascular smooth muscle cell Ca 2ϩ . We tested whether a cGMP-dependent activation of the smooth muscle myosin light chain phosphatase (MLCP) resulting in a Ca 2ϩ desensitization of the contractile apparatus was the underlying mechanism and whether it could be antagonized by the RhoA pathway. Methods and Results-The Ca 2ϩ sensitivity of RA was assessed as the relation between changes in diameter and [Ca 2ϩ ] i in depolarized RA (120 mol/L K ϩ ) exposed to stepwise increases in Ca
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