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Recent studies propose a paracrine role for periadventitial adipose tissue in the regulation of vascular tone. This regulation depends on the anatomical integrity of the periadventitial adipose tissue and involves adipocyte-derived relaxing factor (ADRF). Although the nature of ADRF is largely unknown, it is released by periadventitial adipocytes and induces vasorelaxation by opening [K.sup.+] channels in the plasma membrane of smooth muscle cells. Alterations in the paracrine role of periadventitial adipose tissue might have a role in vascular dysfunction in hypertension and metabolic disease. Therefore, understanding alterations in ADRF release and the [K.sup.+] channels involved will help further our understanding of the increased cardiovascular risk and development of chronic vascular disease in obesity. Furthermore, ADRF and perhaps its putative targets might represent exciting new targets for the development of drugs to treat cardiovascular disorders.

Blood vessels are surrounded by variable amounts of adipose tissue. We showed earlier that adventitial adipose tissue inhibits rat aortic contraction by release of a transferable factor, adventitium-derived relaxing factor (ADRF), which activates smooth muscle [K.sup.+] channels. However, little is known about the mechanisms of ADRF release. Using isolated rat aortic tings and isometric contraction measurements, we show that ADRF release depends on extracellular [[Ca.sup.2+]] (E[C.sub.50] ~ 4.7 mM). ADRF effects do not involve neuronal presynaptic N-type [Ca.sup.2+] and [Na.sup.+] channels or vanilloid, cannabinoid, and CGRP receptors. ADRF release is strongly inhibited by the protein tyrosine kinase inhibitors genistein and tyrphostin A25. In contrast, daidzein, an inactive genistein analog, and the protein tyrosine kinase inhibitor ST63B had no effect. Protein kinase A inhibition by H89 also inhibited ADRF release, whereas the protein kinase G inhibitor KT-5823 had no effect. We propose that ADRF release is [Ca.sup.2+] dependent and is regulated by intracellular signaling pathways involving tyrosine kinase and protein kinase A. Furthermore, ADRF release does not depend on perivascular nerve endings. adipocyte-derived relaxing factor; smooth muscle; tyrosine kinase; protein kinase A; obesity; vascular dysfunction; arterial tone; adventitia-derived relaxing factor

Background: Perivascular adipose tissue (PVAT) exerts anti-contractile effects on visceral arteries by release of various perivascular relaxing factors (PVRFs) and opening voltage-gated K+ (Kv) channels in vascular smooth muscle cells (VSMCs). Palmitic acid methyl ester (PAME) has been proposed as transferable PVRF in rat aorta. Here, we studied PVAT regulation of arterial tone of human mesenteric arteries and clarified the contribution of Kv channels and PAME in the effects. Methods: Wire myography was used to measure vasocontractions of mesenteric artery rings from patients undergoing abdominal surgery. Isolated aortic rings from Sprague-Dawley rats were studied for comparison. PVAT was either left intact or removed from the arterial rings. Vasocontractions were induced by external high K+ (60mM), serotonin (5-HT) or phenylephrine. PAME (10 nM-3μM) was used as vasodilator. Kv channels were blocked by XE991, a Kv7 (KCNQ) channel inhibitor, or by 4-aminopyridine, a non-specific Kv channel inhibitor. PAME was measured in bathing solutions incubated with rat peri-aortic or human visceral adipose tissue. Results: We found that PVAT displayed anti-contractile effects in both human mesenteric arteries and rat aortas. The anti-contractile effects were inhibited by XE991 (30μM). PAME (EC50 ~1.4μM) was capable to produce relaxations of PVAT-removed rat aortas. These effects were abolished by XE991 (30μM), but not 4-aminopyridine (2mM) or NDGA (10μM), a lipoxygenases inhibitor. The cytochrome P450 epoxygenase inhibitor 17-octadecynoic acid (ODYA 10μM) and the soluble epoxide hydrolase inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA 10μM) slightly decreased PAME relaxations. PAME up to 10μM failed to induce relaxations of PVAT-removed human mesenteric arteries. 5-HT induced endogenous PAME release from rat peri-aortic adipose tissue, but not from human visceral adipose tissue. Conclusions: Our data also suggest that Kv7 channels are involved in the anticontractile effects of PVAT on arterial tone in both rat aorta and human mesenteric arteries. PAME could contribute to PVAT relaxations by activating Kv7 channels in rat aorta, but not in human mesenteric arteries. [ABSTRACT FROM AUTHOR]

Background: Hydrogen sulfide (H2S) is a potent vasodilator. However, the complex mechanisms of vasoregulation by H2S are not fully understood. We tested the hypotheses that (1) H2S exerts vasodilatory effects by opening KCNQ-type voltage-dependent (Kv) K+ channels and (2) that H2S-producing cystathionine- γ-lyase (CSE) in perivascular adipose tissue plays a major role in this pathway. Methodology/Principal Findings: Wire myography of rat and mouse aortas was used. NaHS and 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) were used as H2S donors. KCNQ-type Kv channels were blocked by XE991. 4-Propargylglycine (PPG) and β-cyano-l-alanine (BCA), or 2- (aminooxy)-acetic acid (AOAA) were used as inhibitors of CSE or cystathionine- β-synthase (CBS), respectively. NaHS and ADTOH produced strong vasorelaxation in rat and mouse aortas, which were abolished by KCNQ channel inhibition with XE991. Perivascular adipose tissue (PVAT) exerted an anticontractile effect in these arteries. CSE inhibition by PPG and BCA reduced this effect in aortas from rats but not from mice. CBS inhibition with AOAA did not inhibit the anticontractile effects of PVAT. XE991, however, almost completely suppressed the anticontractile effects of PVAT in both species. Exogenous I-cysteine, substrate for the endogenous production of H2S, induced vasorelaxation only at concentrations >5 mmol/I, an effect unchanged by CSE inhibition. Conclusions/Signficance: Our results demonstrate potent vasorelaxant effects of H2S donors in large arteries of both rats and mice, in which XE991-sensitive KCNQ-type channel opening play a pivotal role. CSE-H2S seems to modulate the effect of adipocyte-derived relaxing factor in rat but not in mouse aorta. The present study provides novel insight into the interaction of CSE-H2S and perivascular adipose tissue. Furthermore, with additional technical advances, a future clinical approach targeting vascular H2S/KCNQ pathways to influence states of vascular dysfunction may be possible. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor(s) (ADRF) that opens Kv channels in rat arteries. Visceral fat accumulation causes adipocyte dysfunction, including hyposecretion of adiponectin. We tested the hypothesis that ADRF might be adiponectin and that adiponectin plays a role in the paracrine control of vascular tone by perivascular adipose tissue. Methods and results: We studied Sprague–Dawley rats, wild-type and adiponectin gene-deficient (Apn 1−/−) mice, and New Zealand obese (NZO) mice. In rat aortas, recombinant adiponectin at serum levels (2–5 μg/ml) inhibited serotonin-induced contractions. The effects were abolished by Kv channel inhibition with 4-aminopyridine (4-AP, 2 mM). Similar effects were observed in NZO mouse mesenteric arteries. To study vascular function in Apn 1−/− mice, the mesenteric vascular bed was isolated, cannulated, and perfused at a constant 4–5-ml/min flow in the absence and presence of serotonin. 4-AP (2 mM) induced a similar increase in perfusion pressure in the Apn 1−/− perfused isolated mesenteric vascular bed, compared to wild-type mice. Removal of perivascular fat increased the vasoconstrictor responses, but abolished the 4-AP effects. The anti-contractile effects of perivascular fat were similar in mesenteric artery and aortic rings from Apn 1−/− and wild-type mice. Despite high adiponectin levels, the anti-contractile effects of perivascular fat were diminished in mesenteric arteries of NZO mice with age. Conclusion: Adiponectin is a novel humoral vasodilator that relaxes aortic and mesenteric rings by opening Kv channels. Similar to the rat, perivascular adipose tissue of the mouse harbors an ADRF, which is malfunctional in NZO mice and is not adiponectin. [Copyright &y& Elsevier]

A correction to the article "Increased Vascular Smooth Muscle Contractility in TRPC6‾/‾ Mice," that was published in the Volume 25, no.16, 2005 issue is presented.

Hydrogen sulfide is the "third" gasotransmitter on the rise in cardiovascular research. Recent studies show that hydrogen sulfide has a great potential in the regulation of vascular tone of systemic arteries and many molecular targets are discussed. However, the complex mechanism of vascular tone regulation by hydrogen sulfide is only incompletely understood. It seems that a potent interaction of hydrogen sulfide with vascular endothelial growth factor (VEGF) becomes important in angiogenesis, in the process of wound healing, but also in tumor angiogenesis. Hydrogen sulfide exerts anti-inflammatory effects and it could be a pharmacological target in vascular dysfunction in association with obesity-related hypertension as well as in tumor development and progression. However, the underlying molecular pathways still need to be revealed. This review primarily focuses on the regulatory role of hydrogen sulfide in controlling vascular tone. We attempt to provide recent insights into mechanisms by which CSE-dependent hydrogen sulfide plays a role in the regulation of vascular tone by perivascular adipose tissue. The role of KCNQ channels and other ionic permeation pathways as key targets will be discussed. Recent findings which are summarized in this paper provide new insights into molecular mechanisms of hydrogen sulfide that are crucial for understanding vascular dysfunction in cardiovascular disease and possibly angiogenesis. Future research will be extended to investigate the therapeutic potential of hydrogen sulfide and their targets such as KCNQ channels in cardiovascular diseases, angiogenesis and tumor genesis.