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Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse.

ABSTRACT: OBJECTIVE: Patients with diabetic erectile dysfunction often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. We examined the effectiveness of the potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, in promoting cavernous endothelial regeneration and restoring erectile function in diabetic animals. RESEARCH DESIGN AND METHODS: Four groups of mice were used: controls; streptozotocin (STZ)-induced diabetic mice; STZ-induced diabetic mice treated with repeated intracavernous injections of PBS; and STZ-induced diabetic mice treated with COMP-Ang1 protein (days -3 and 0). Two and 4 weeks after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations, Western blot analysis, and cGMP quantification. We also performed a vascular permeability test. RESULTS: Local delivery of the COMP-Ang1 protein significantly increased cavernous endothelial proliferation, endothelial nitric oxide (NO) synthase (NOS) phosphorylation, and cGMP expression compared with that in the untreated or PBS-treated STZ-induced diabetic group. The changes in the group that received COMP-Ang1 restored erectile function up to 4 weeks after treatment. Endothelial protective effects, such as marked decreases in the expression of p47(phox) and inducible NOS, in the generation of superoxide anion and nitrotyrosine, and in the number of apoptotic cells in the corpus cavernosum tissue, were noted in COMP-Ang1-treated STZ-induced diabetic mice. An intracavernous injection of COMP-Ang1 completely restored endothelial cell-cell junction proteins and decreased cavernous endothelial permeability. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished by the NOS inhibitor, N-nitro-L-arginine methyl ester, but not by the NADPH oxidase inhibitor, apocynin. CONCLUSIONS: These findings support the concept of cavernous endothelial regeneration by use of the recombinant Ang1 protein as a curative therapy for diabetic erectile dysfunction.

SUBMITTER: Jin HR

PROVIDER: S-EPMC3046858 | biostudies-other | 2011 Mar

REPOSITORIES: biostudies-other

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Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse.

Jin Hai-Rong HR Kim Woo Jean WJ Song Jae Sook JS Piao Shuguang S Choi Min Ji MJ Tumurbaatar Munkhbayar M Shin Sun Hwa SH Yin Guo Nan GN Koh Gou Young GY Ryu Ji-Kan JK Suh Jun-Kyu JK

Diabetes 20110126 3

<h4>Objective</h4>Patients with diabetic erectile dysfunction often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. We examined the effectiveness of the potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, in promoting cavernous endothelial regeneration and restoring erectile function in diabetic animals.<h4>Research design and methods</h4>Four groups of mice were used: controls; streptozotocin (STZ)-induced diabeti ...[more]

PMID: 21270241

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Project description:The efficacy of statins is related to the 'common soil' hypothesis, which proposes oxidative stress and inflammation as main pathophysiologic processes in the disease group of diabetes and endothelial dysfunction. This study evaluated the recovery of erectile function after administration of chronic statin alone in streptozotocin (STZ)-induced diabetes mellitus (DM) rats, focusing on the anti-oxidative effects and consequentially recuperated endothelial function. A total of 45 male Sprague-Dawley rats (8 weeks old) were divided into three groups (n = 15 each): an age-matched normal control group (Control group), an uncontrolled DM group (DM group), and a statin-treated group (Statin group). The rats in the DM and Statin group received an injection of STZ (60 mg/kg). Beginning 10 weeks after the establishment of DM, the Statin group received daily treatment with atorvastatin (10 mg/kg) via oral gavage for four weeks. After 14 weeks, the results of the experiment were evaluated. The ratios of intracavernosal pressure (ICP) to mean arterial pressure (MAP) were recorded with cavernosometry (20 Hz, 3 V, 0.2 msec for 30 seconds) before and after the intravenous administration of udenafil (1 mg/kg). Expression of alpha-smooth muscle actin (α-SMA) was evaluated using cavernosal tissue. In addition, changes in RhoA translocation ratio and myosin phosphatase target subunit 1 (MYPT1) phosphorylation were evaluated with western blot. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were also analyzed as measurements of oxidative stress levels. The ICP/MAP and area under the curve (AUC)/MAP ratios of the Statin group were obviously superior to the DM group, but were not comparable to the Control group (P<0.001). The level of oxidative stress, namely SOD activity, was also significantly lower in the Statin group than in the DM group (P = 0.015), and was comparable to the Control group. In contrast, MDA levels were not considerably different among the groups (P = 0.217). The RhoA translocation ratio was not significantly different among the groups (P = 0.668), whereas MYPT1 phosphorylation in the Statin group was significantly lower than in the DM group (P = 0.030), and similar to the Control group. Expression of α-SMA in the Statin group was higher than in the DM group (P<0.001), and comparable to the Control group. Chronic statin treatment alone showed anti-oxidative effects and helped to restore the erectile mechanism, but did not lead to the full recovery of erectile function in STZ-induced DM rats. Therefore, combination therapy rather than a single agent should be the preferred treatment strategy for DM-associated erectile dysfunction, especially in the setting of severe diabetes.

Dataset Information

Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse.

Publications

Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse.

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