The sympathetic nervous system and its neurotransmitter effectors are undeniably important to blood pressure control. We made the novel discovery that perivascular adipose tissue (PVAT) contains significant concentrations of catecholamines. We hypothesized that PVAT contains sufficient releasable catecholamines to affect vascular function. HPLC, isometric contractility, immunohistochemistry, whole animal approaches and pharmacology were used to test this hypothesis. In normal rat thoracic aorta and superior mesenteric artery, the indirect sympathomimetic tyramine caused a concentration-dependent contraction that was dependent on the presence of PVAT. Tyramine stimulated release of NA, dopamine (DA) and the tryptamine serotonin (5-HT) from PVAT isolated from both arteries. In both arteries, tyramine-induced concentration-dependent contraction was rightward-shifted and reduced by the noradrenaline transporter inhibitor nisoxetine (1 μM), the vesicular monoamine transporter tetrabenazine (10 μM) and abolished by the α adrenoreceptor antagonist prazosin (100 nM). Inhibitors of the DA and 5-HT transporter did not alter tyramine-induced, PVAT-dependent contraction. Removal of the celiac ganglion as a neuronal source of catecholamines for superior mesenteric artery PVAT did not significantly reduce the maximum or shift the concentration dependent contraction to tyramine. Electrical field stimulation of the isolated aorta was not affected by the presence of PVAT. These data suggest that PVAT components that are independent of sympathetic nerves can release NA in a tyramine-sensitive manner to result in arterial contraction. Because PVAT is intimately apposed to the artery, this raises the possibility of local control of arterial function by PVAT catecholamines.

Xavier-Ferrucio and colleagues elucidate the mechanism of thrombocytosis in iron deficiency anemia, using murine and human cell models to demonstrate that iron deficiency attenuates ERK signaling and biases the commitment of megakaryocyte-erythrocyte progenitors toward the megakaryocytic lineage.

Watts SW. Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue. Am J Physiol Heart Circ Physiol 309: H1904 -H1914, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00308.2015.-Perivascular adipose tissue (PVAT) reduces vasoconstriction to norepinephrine (NE). A mechanism by which PVAT could function to reduce vascular contraction is by decreasing the amount of NE to which the vessel is exposed. PVATs from male Sprague-Dawley rats were used to test the hypothesis that PVAT has a NE uptake mechanism. NE was detected by HPLC in mesenteric PVAT and isolated adipocytes. Uptake of NE (10 M) in mesenteric PVAT was reduced by the NE transporter (NET) inhibitor nisoxetine (1 M, 73.68 Ϯ 7.62%, all values reported as percentages of vehicle), the 5-hydroxytryptamine transporter (SERT) inhibitor citalopram (100 nM) with the organic cation transporter 3 (OCT3) inhibitor corticosterone (100 M, 56.18 Ϯ 5.21%), and the NET inhibitor desipramine (10 M) with corticosterone (100 M, 61.18 Ϯ 6.82%). Aortic PVAT NE uptake was reduced by corticosterone (100 M, 53.01 Ϯ 10.96%). Confocal imaging of mesenteric PVAT stained with 4-[4-(dimethylamino)-styrl]-N-methylpyridinium iodide (ASP ϩ ), a fluorescent substrate of cationic transporters, detected ASP ϩ uptake into adipocytes. ASP ϩ (2 M) uptake was reduced by citalopram (100 nM, 66.68 Ϯ 6.43%), corticosterone (100 M, 43.49 Ϯ 10.17%), nisoxetine (100 nM, 84.12 Ϯ 4.24%), citalopram with corticosterone (100 nM and 100 M, respectively, 35.75 Ϯ 4.21%), and desipramine with corticosterone (10 and 100 M, respectively, 50.47 Ϯ 5.78%). NET protein was not detected in mesenteric PVAT adipocytes. Expression of Slc22a3 (OCT3 gene) mRNA and protein in PVAT adipocytes was detected by RT-PCR and immunocytochemistry, respectively. These end points support the presence of a transporter-mediated NE uptake system within PVAT with a potential mediator being OCT3. PERIVASCULAR ADIPOSE TISSUE (PVAT) closely envelops many blood vessels of the body (65). This relationship between PVAT and the blood vessel has earned PVAT its place as the fourth layer of the blood vessel, the "tunica adiposa" (14). Beyond providing structural support, PVAT has many roles in modulating blood vessel function (68). The release of vasoactive molecules from PVAT influences vascular function by altering the proliferation, migration, inflammation, and contraction of vascular smooth muscle (9, 20 -22, 24, 46, 68, 72). Interestingly, a releasable pool of catecholamines is present in PVAT (5, 67). Although both contractile and anticontractile substances can be released from PVAT (9,22,24,25,72), the presence of PVAT on blood vessels generally reduces vessel contraction in response to various agonists, including norepinephrine (NE) (64). Knowledge on how these mechanisms interact to influence the anticontractile properties of PVAT in NE-induced contraction is not complete (36).The anticontractile effect of PVAT is lost in obesity and hypertension, implicating PVAT as an integral lin...

The mechanisms by which phlebotomy promotes the mobilization of hepatic iron stores are not well understood. NCOA4 (nuclear receptor coactivator 4) is a widely-expressed intracellular protein previously shown to mediate the autophagic degradation of ferritin. Here, we investigate a local requirement for NCOA4 in the regulation of hepatic iron stores and examine mechanisms of NCOA4 regulation. Hepatocyte-targeted Ncoa4 knockdown in non-phlebotomized mice had only modest effects on hepatic ferritin subunit levels and non-heme iron concentration. After phlebotomy, mice with hepatocyte-targeted Ncoa4 knockdown exhibited anemia and hypoferremia similar to control mice with intact Ncoa4 regulation, but showed a markedly impaired ability to lower hepatic ferritin subunit levels and hepatic non-heme iron concentration. This impaired hepatic response was observed even when dietary iron was limited. In both human and murine hepatoma cell lines, treatment with chemicals that stabilize hypoxia inducible factor (HIF), including desferrioxamine, cobalt chloride, and dimethyloxalylglycine, raised NCOA4 mRNA. This NCOA4 mRNA induction occurred within 3 hours, preceded a rise in NCOA4 protein, and was attenuated in the setting of dual HIF-1a and HIF-2a knockdown. In summary, we show for the first time that NCOA4 plays a local role in facilitating iron mobilization from the liver after blood loss and that HIF regulates NCOA4 expression in cells of hepatic origin. Because the prolyl hydroxylases that regulate HIF stability are oxygen and iron-dependent enzymes, our findings suggest a novel mechanism by which hypoxia and iron deficiency may modulate NCOA4 expression to impact iron homeostasis.

There are sex associated differences in the risk for cardiovascular comorbidities in obesity and metabolic syndrome. A common clinical finding in these diseases is the expansion of perivascular adipose tissues (PVAT) which is associated with alterations in their role as regulators of vessel function. PVAT hyperplasia and hypertrophy are dependent on the biology of populations of adipocyte progenitor cells (APC). It is currently unclear if PVAT enlargement diverges between males and females and the mechanisms linking APC biology with sexual dimorphism remain poorly understood. This study tested the hypothesis that vessel location and sexual dimorphism affect the distribution and adipogenic capacity of APC in cardiovascular disease risk relevant PVAT sites. PVAT from thoracic aorta (aPVAT) and mesenteric resistance arteries (mPVAT) was collected from 10‐week‐old female and male Sprague–Dawley rats. Differences in APC distribution in stromal vascular fraction cells from PVAT were determined. APC were defined as cells expressing CD34, CD44, and platelet derived growth factor α. In both sexes aPVAT had fewer APC compared to mPVAT and perigonadal adipose tissue (GON). Sex‐related differences were observed in the expression of CD34, where females had fewer CD34+ cells in PVATs. APC proliferation and adipogenic capacity in vitro were not affected by sex. However, APC from aPVAT had a lower proliferation capacity compared to mPVAT. These data demonstrate that the distribution of APC within PVAT exhibits sexual dimorphism and is affected by anatomical location.