Combined Angiopoietin-1 and vascular endothelial growth factor gene transfer restores cavernous angiogenesis and erectile function in a rat model of hypercholesterolemia

Ryu, Ji-Kan,Cho, Chung-Hyun,Shin, Hwa-Yean,Song, Sun U.,Oh, Seung-Min,Lee, Minhyung,Piao, Shuguang,Han, Jee-Young,Kim, In-Hoo,Koh, Gou Young,Suh, Jun-Kyu Elsevier 2006 MOLECULAR THERAPY Vol.13 No.4

<P><B>Abstract</B></P><P>Hypercholesterolemia-related endothelial cell dysfunction and decreased endothelium-derived nitric oxide formation may account for impaired angiogenesis and subsequent erectile dysfunction. Angiopoietin-1 (Ang1) is a critical angiogenic factor for vascular maturation and enhances vascular endothelial growth factor (VEGF)-induced angiogenesis in a complementary manner. We hypothesized that combined adenovirus-delivered human Ang1 (ad-Ang1) and VEGF165 (ad-VEGF165) gene transfer might promote angiogenesis cooperatively in a rat model of hypercholesterolemic erectile dysfunction and result in a recovery of erectile function. Ad-Ang1 and ad-VEGF165 were injected either alone or in combination into the corpus cavernosum of the penis. Combined gene transfer of both ad-Ang1 and ad-VEGF165 significantly increased cavernous angiogenesis, eNOS phosphorylation, and cGMP expression compared with that in the groups treated with either therapy alone. Erectile function, as evaluated by electrical stimulation of the cavernous nerve 2 and 8 weeks after treatment, was completely restored in the combined treatment group, whereas intracavernous injection of either ad-Ang1 or ad-VEGF165 alone elicited partial improvement. The results indicate that combined application of angiogenic factors may enhance cavernous angiogenesis cooperatively by reinforcing the endothelium both structurally and functionally, which results in an additive effect on erectile function in hypercholesterolemic rats.</P>

Androgens Modulate Endothelial Function and Endothelial Progenitor Cells in Erectile Physiology

Abdulmaged M. Traish,Artin Galoosian 대한비뇨의학회 2013 Investigative and Clinical Urology Vol.54 No.11

The incidence of erectile dysfunction (ED) increases with age and cardiovascular disease risk factors, such as hypertension, hyperlipidemia, insulin resistance, obesity, and diabetes. These risk factors are thought to contribute to endothelial dysfunction and atherosclerosis, thus contributing to the pathophysiology of ED. The role of the endothelium in regulating erectile physiology is well established. However, the role of androgens in modulating endothelial function and endothelial repair mechanisms subsequent to vascular injury in erectile tissue remains a subject of intensive research. The clinical and preclinical evidence discussed in this review suggests that androgens regulate endothelial function and also play an important role in the development and maturation of endothelial progenitor cells (EPCs), which are thought to play a critical role in repair of endothelial injury in vascular beds. In this review, we discuss the data available on the effects of androgens on endothelial function and EPCs in the repair of vascular injury. Indeed, more research is needed to fully understand the molecular and cellular basis of androgen action in regulating the development, differentiation, maturation, migration, and homing of EPCs to the site of injury. A better understanding of these processes will be critical to the development of new therapeutic approaches to the treatment of vascular ED.

S-Adenosyl Methionine Prevents Endothelial Dysfunction by Inducing Heme Oxygenase-1 in Vascular Endothelial Cells

김선영,고은희,홍석우,김미옥,김현식,장정은,임재찬,박인선,이기업 한국분자세포생물학회 2013 Molecules and cells Vol.36 No.4

S-adenosyl methionine (SAM) is a key intermediate in the metabolism of sulfur amino acids and is a major methyl donor in the cell. Although the low plasma level of SAM has been associated with atherosclerosis, the effect of SAM administration on atherosclerosis is not known. Endothelial dysfunction is an early prerequisite for atherosclerosis. This study was undertaken to investigate the possible preventive effect of SAM on endothelial dysfunction and the molecular mechanism of its action. SAM treatment prevented endothelial dysfunction in high fat diet (HFD)-fed rats. In cultured human aortic endothelial cells, linoleic acid (LA) increased and SAM decreased cell apoptosis and endoplasmic reticulum stress. Both LA and SAM increased heme oxygenase-1 (HO-1) expression in an NF-E2-related factor 2-dependent manner. However, knoc-kdown of HO-1 reversed only the SAM-induced pre-ventive effect of cell apoptosis. The LA-induced HO-1 expression was dependent on PPAR, whereas SAM in-duced HO-1 in a PPAR-independent manner. These data demonstrate that SAM treatment prevents endothelial dysfunction in HFD-fed animals by inducing HO-1 in vascular endothelial cells. In cultured endothelial cells, SAM-induced HO-1 was res-ponsible for the observed prevention of cell apoptosis. We propose that SAM treatment may represent a new therapeutic strategy for atherosclerosis.

Endothelial arginase II and atherosclerosis

유승우,Dan E. Berkowitz,임현교 대한마취통증의학회 2011 Korean Journal of Anesthesiology Vol.61 No.1

Atherosclerotic vascular disease is the leading cause of morbidity and mortality in developed countries. While it is a complex condition resulting from numerous genetic and environmental factors, it is well recognized that oxidized low-density lipoprotein produces pro-atherogenic effects in endothelial cells (ECs) by inducing the expression of adhesion molecules, stimulating EC apoptosis, inducing superoxide anion formation and impairing protective endothelial nitric oxide (NO) formation. Emerging evidence suggests that the enzyme arginase reciprocally regulates NO synthase and NO production by competing for the common substrate L-arginine. As oxidized LDL (OxLDL)results in arginase activation/upregulation, it appears to be an important contributor to endothelial dysfunction by a mechanism that involves substrate limitation for endothelial NO synthase (eNOS) and NO synthesis. Additionally,arginase enhances production of reactive oxygen species by eNOS. Arginase inhibition in hypercholesterolemic (ApoE^(-/-) mice or arginase II deletion (ArgII^(-/-) mice restores endothelial vasorelaxant function, reduces vascular stiffness and markedly reduces atherosclerotic plaque burden. Furthermore, arginase activation contributes to vascular changes including polyamine-dependent vascular smooth muscle cell proliferation and collagen synthesis. Collectively, arginase may play a key role in the prevention and treatment of atherosclerotic vascular disease.

Effect of Rosiglitazone in Sodium Arsenite-induced Experimental Vascular Endothelial Dysfunction

Tajpreet Kaur,Rajesh Kumar Goel,Pitchai Balakumar 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.4

The present study has been designed to investigate the effect of rosiglitazone, a peroxisome proliferator activated receptor γ agonist in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. The rats were administered sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) to induce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum nitrite/nitrate concentration. Further,the integrity of the aortic endothelium was assessed histologically using haematoxylin-eosin staining. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances, aortic reactive oxygen species and reduced form of glutathione. The administration of sodium arsenite produced VED by impairing acetylcholine-induced endothelium dependent relaxation, diminishing the integrity of vascular endothelium and decreasing the serum nitrite/nitrate concentration. In addition, sodium arsenite was noted to produce oxidative stress as it increased serum thiobarbituric acid reactive substances and aortic reactive oxygen species and consequently decreased glutathione. Treatment with rosiglitazone (3 mg/kg/day, p.o., 2 weeks and 5 mg/kg/day, p.o., 2 weeks) significantly prevented sodium arsenite-induced VED by enhancing acetylcholine-induced endothelium dependent relaxation, improving the integrity of vascular endothelium, increasing the nitrite/nitrate concentration and decreasing the oxidative stress. However, the vascular protective effect of rosiglitazone was markedly abolished by co-administration of nitric oxide synthase inhibitor, N-Omega-Nitro-L-Arginine Methyl Ester (L-NAME) (25 mg/kg/day, i.p., 2 weeks). Thus, it may be concluded that rosiglitazone reduces oxidative stress, activates eNOS and enhances the generation of nitric oxide to prevent sodium arsenite-induced VED in rats.

Inhalation exposure to cigarette smoke induces endothelial nitric oxide synthase uncoupling and enhances vascular collagen deposition in streptozotocin-induced diabetic rats

Do, Van Quan,Park, Kwang-Hoon,Seo, Yoon-Seok,Park, Jung-Min,Kim, Bumseok,Kim, Sang-Kyum,Sung, Jae Hyuck,Lee, Moo-Yeol Elsevier 2020 Food and chemical toxicology Vol.136 No.-

<P><B>Abstract</B></P> <P>Smoking is an acknowledged risk factor for vascular disorders, and vascular complication is a main outcome of diabetes. Hence, we investigated the impact of cigarette smoke on blood vessels in diabetes, postulating that smoking might aggravate diabetic vascular impairment. Sprague–Dawley rats were divided into four groups: control, cigarette smoke-exposed, diabetic, and cigarette smoke-exposed diabetic groups. Streptozotocin-induced diabetic rats were exposed to cigarette smoke by inhalation at total particulate matter concentration of 200 μg/L for 4 h/day, 5 day/week for a total of 4 weeks. Diabetes caused structural change of aorta, but additional cigarette smoke exposure did not induce further alteration. Collagen, a marker for fibrosis, was increased in media of diabetic aorta, and this increase was augmented by cigarette smoke. Cigarette smoke induced endothelial nitric oxide synthase (eNOS) uncoupling in the diabetic group. Malondialdehyde was increased and glutathione was decreased in blood from diabetes, but these effects were not exaggerated by cigarette smoke. Cigarette smoke caused NADPH oxidase (NOX) 2 expression in diabetic aorta and enhanced diabetes-induced NOX4 expression in aorta. Taken together, cigarette smoke exposure can aggravate vascular fibrosis and induce eNOS uncoupling in diabetes under experimental condition, suggesting that smoking might exacerbate diabetic vascular impairments.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Impact of cigarette smoke on the progress of diabetic vascular impairment was investigated. </LI> <LI> Diabetes-induced structural change of aorta was minimally affected by cigarette smoke exposure. </LI> <LI> Cigarette smoke induced endothelial nitric oxide synthase (eNOS) uncoupling in diabetic aortas. </LI> <LI> Cigarette smoke further enhanced diabetes-caused collagen deposition in aorta. </LI> <LI> Cigarette smoke exposure induced NADPH oxidase (NOX) 2 and increased NOX4 expression in diabetic aorta. </LI> </UL> </P>

Expression Profile of Neuro-Endocrine-Immune Network in Rats with Vascular Endothelial Dysfunction

Li, Lujin,Jia, Zhenghua,Xu, Ling,Wu, Yiling,Zheng, Qingshan The Korean Society of Pharmacology 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.2

This study was to determine the correlation between endothelial function and neuro-endocrine-immune (NEI) network through observing the changes of NEI network under the different endothelial dysfunction models. Three endothelial dysfunction models were established in male Wistar rats after exposure to homocysteine (Hcy), high fat diet (HFD) and Hcy+HFD. The results showed that there was endothelial dysfunction in all three models with varying degrees. However, the expression of NEI network was totally different. Interestingly, treatment with simvastatin was able to improve vascular endothelial function and restored the imbalance of the NEI network, observed in the Hcy+HFD group. The results indicated that NEI network may have a strong association with endothelial function, and this relationship can be used to distinguish different risk factors and evaluate drug effects.

Expression Profile of Neuro-Endocrine-Immune Network in Rats with Vascular Endothelial Dysfunction

Lujin Li,Yiling Wu,Qingshan Zheng,Zhenghua Jia,Ling Xu 대한약리학회 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.2

This study was to determine the correlation between endothelial function and neuro-endocrineimmune(NEI) network through observing the changes of NEI network under the different endothelialdysfunction models. Three endothelial dysfunction models were established in male Wistar rats afterexposure to homocysteine (Hcy), high fat diet (HFD) and Hcy+HFD. The results showed that therewas endothelial dysfunction in all three models with varying degrees. However, the expression of NEInetwork was totally different. Interestingly, treatment with simvastatin was able to improve vascularendothelial function and restored the imbalance of the NEI network, observed in the Hcy+HFD group. The results indicated that NEI network may have a strong association with endothelial function, andthis relationship can be used to distinguish different risk factors and evaluate drug effects.

MicroRNAs as critical regulators of the endothelial to mesenchymal transition in vascular biology

( Jongmin Kim ) 생화학분자생물학회 2018 BMB Reports Vol.51 No.2

The endothelial to mesenchymal transition (EndMT) is a newly recognized, fundamental biological process involved in development and tissue regeneration, as well as pathological processes such as the complications of diabetes, fibrosis and pulmonary arterial hypertension. The EndMT process is tightly controlled by diverse signaling networks, similar to the epithelial to mesenchymal transition. Accumulating evidence suggests that microRNAs (miRNAs) are key regulators of this network, with the capacity to target multiple messenger RNAs involved in the EndMT process as well as in the regulation of disease progression. Thus, it is highly important to understand the molecular basis of miRNA control of EndMT. This review highlights the current fund of knowledge regarding the known links between miRNAs and the EndMT process, with a focus on the mechanism that regulates associated signaling pathways and discusses the potential for the EndMT as a therapeutic target to treat many diseases. [BMB Reports 2018; 51(2): 65-72]

Protective Effects of Grape Juice on Vascular Damage Induced by Chlorine Free Radical in Rats

Jose Britto Junior,Diego Antonio Costa Arantes,Karla Carnerio Siqueira Leite,Eric de Souza Gil,Matheus Lavorenti Rocha 한국식품영양과학회 2021 Preventive Nutrition and Food Science Vol.26 No.4

Grapes and their derivatives have antioxidant and cardioprotective properties. Therefore, we hypothesized that grape juice (GJ) could improve vascular oxidative damage caused by chlorine radicals (OCl<SUP>−</SUP>), which are excessively produced in vascular tissue during cardiovascular diseases (mainly diabetes and hypertension). The antioxidant capacity of GJ was analyzed by an electrochemical method, followed by administration in rats (100 or 300 mg/kg/d, via the oral) for seven days. Then, rats were sacrificed, and their aortas were isolated and subjected to isometric recordings or immunohistochemical analyses with or without exposure to OCl<SUP>−</SUP> (5, 20, or 100 μM, 60 min). Concentration-effect curves for acetylcholine (ACh) and sodium nitroprusside (SNP) were derived to analyze endothelium-dependent or independent vasorelaxation. The GJ presented with high antioxidant capacity, and treatment with GJ did not alter vascular relaxation induced by ACh or SNP. After exposure to OCl<SUP>−</SUP>, endothelium-denuded arteries showed preserved relaxation with SNP, whereas endothelium-intact arteries showed reduced relaxation with ACh. OCl<SUP>−</SUP> at various concentrations induced significantly decreased relaxation of arteries (80.6±4.2%, 55.4±4.7%, and 28.1±5.9%, respectively) vs. control arteries (96.8±2.4%). However, treatment with GJ prevented loss in relaxation caused by 5 and 20 μM OCl<SUP>−</SUP> and improved relaxation after exposure to 100 μM OCl<SUP>−</SUP>. Exposure to OCl<SUP>−</SUP> induced increased nitrotyrosine immunostaining of endothelial cell layers, which was improved by GJ treatment. Altogether, vascular damage caused by OCl<SUP>−</SUP> was prevented by treatment with GJ, and GJ prevented nitrosative stress in these vessels.