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1 The isometric response to arginine-vasopressin (10-1o 10-7 M) was studied in 2 mm long rabbit arterial segments isolated from several vascular beds (cutaneous, pial, renal, coronary, muscular, mesenteric and pulmonary). 2 Vasopressin induced contraction in central ear (cutaneous), basilar (pial), renal, coronary and saphenous (muscular) arteries, but had no effect in mesenteric and pulmonary arteries; the order of potency for the contraction was: ear > basilar > renal > coronary > saphenous arteries. 3 Treatment with the blocker of nitric oxide synthesis NG-nitro-L-arginine methyl ester (L-NAME; 106-I0-M) increased significantly (P< 0.05) the contraction to vasopressin in ear (148% of control), basilar (150% of control), renal (304% of control), coronary (437% of control) and saphenous (235% of control) arteries. Removal of the endothelium increased significantly (P<0.05) the contraction to vasopressin in basilar (138% of control), renal (253% of control), coronary (637% of control) and saphenous (662% of control) arteries, but not in ear artery. Mesenteric and pulmonary arteries in the presence of L-NAME or after endothelium removal did not respond to vasopressin, as occurred in control conditions. 4 The specific antagonist for V1 vasopressin receptors d(CH2)5Tyr(Me)AVP (3 x 10-9-10-7 M) was more potent (pA2=9.3-10.1) than the antagonist for both VI and V2 vasopressin receptors desGly-d(CH2)5-D-Tyr(Et)ValAVP (10-7-10-6 M) (pA2 =7.4-8.4) to block the contraction to vasopressin of ear, basilar, renal and coronary arteries. 5 The specific V2 vasopressin agonist [deamino-Cys1, D-Arg8]-vasopressin (desmopressin) (10-1o-10-7 M) did not produce any effect in any of the arteries studied, with or without endothelium. 6 In arteries precontracted with endothelin-1, vasopressin or desmopressin did not produce relaxation. 7 These results suggest: (a) most arterial beds studied (5 of 7) exhibit contraction to vasopressin with different intensity; (b) the vasoconstriction to this peptide is mediated mainly by stimulation of V1 vasopressin receptors, and (c) endothelial nitric oxide may inhibit the vasoconstriction to this peptide, especially in coronary and renal vasculatures.

Summary Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.

1 The role of the endothelium in the effects of cooling on the response to cholinoceptor stimulation of the rabbit central ear (cutaneous) and femoral (non-cutaneous) arteries was studied using 2 mm long cylindrical segments.2 Concentration-response curves for acetylcholine (I0-9-IO-OM), methacholine (10-9-1iO-M) and sodium nitroprusside (IO-9-IO-4M) were isometrically recorded in arteries under conditions, with and without endothelium or following pretreatment with the nitric oxide-synthesis inhibitor N0-nitro-Larginine methyl ester (L-NAME, 10-6-3 x 10-M) at 37°C and at 24°C (cooling). 3 Ear and femoral arteries showed endothelium-dependent relaxation to acetylcholine and methacholine at 37°C and 24°C. The extent of relaxation of the control ear arteries, but not of the control femoral arteries, to acetylcholine and methacholine increased during cooling. 4 L-NAME (10-6-3 x IO-4 M) reduced in a concentration-dependent way the response of ear arteries to acetylcholine at both 37°C and 24°C, this reduction being more potent at 37°C. L-Arginine (10-'-10-M) reversed in a concentration-dependent manner the inhibitor effects of 10-5 M L-NAME at both temperatures. 5 Sodium nitroprusside caused a concentration-dependent relaxation in both arteries that was endothelium-independent. However, the extent of relaxation to this nitrovasodilator in ear and femoral arteries was lower at 24°C. 6 These results suggest that cooling augments the reactivity of cutaneous (ear) arteries, but not that of non-cutaneous (femoral) arteries to cholinoceptor stimulation by endothelium-mediated mechanisms. Cooling could therefore facilitate the stimulated release of endothelial nitric oxide in cutaneous vessels.

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