Aging-related induction of inducible nitric oxide synthase is vasculo-protective to the arterial media

Ferrini, Mónica G.

doi:10.1016/j.cardiores.2003.12.006

Cited by 86 publications

(100 citation statements)

References 41 publications

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“…3). This results suggest an enhanced oxidative stress in VSMCs from the late-passages which is consistent with the previous reports [21,35]. However, IGF-1 exposure (10 ng/ml) failed to enhance ROS formation in cells from either the early or late passages.…”

Section: Migration and Proliferation Of Different Passage Vsmcssupporting

confidence: 93%

Impact of Insulin-like Growth Factor-I on Migration, Proliferation and Akt-ERK Signaling in Early and Late-passages of Vascular Smooth Muscle Cells

et al. 2007

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Migration and proliferation of vascular smooth muscle cells (VSMCs) are important events in the progression of atherosclerosis. Insulin-like growth factor I (IGF-1) possesses both antiapoptotic and mitogenic/motogenic effects in VSMCs although the influence of life cycle on IGF-1-induced effects is unclear. This study was designed to evaluate the effect of IGF-1 on migration, proliferation, and signaling mechanisms in VSMCs from early (3-5) to late (20-22) passages. Migration, proliferation, and cell survival were measured using monolayer wounding, 3 [H]-thymidine incorporation and MTT assay, respectively. Akt and ERK, which are critical to proliferation, differentiation and migration, were examined using Western blot analysis. DCF-DA fluorescence was used to quantify Reactive Oxygen Species (ROS) production. Latepassage VSMCs exhibited significantly higher basal cell proliferation and enhanced sensitivity to IGF-1-stimulated migration compared to cells from early-passages. Phosphorylated Akt and ERK levels were significantly higher in late-passage cells compared to early-passage, which was further enhanced by IGF-1 treatment. Late-passage cells exhibited higher levels of ROS production compared to early-passage, cells. IGF-1 did not significantly alter ROS levels in either passage. Expression of the cell cycle regulator p53, p21, and p16 was not affected by repeated passaging of cells. These results indicated that repeated passaging of VSMCs exhibits a phenotype which has higher proliferative capacity. Activation of trophic signaling molecules such as ERK1/2 and Akt and generation of ROS may represent the mechanisms by which repeated passages of VSMCs acquire a motogenic and mitogenic phenotype.

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Section: Migration and Proliferation Of Different Passage Vsmcssupporting

confidence: 93%

Impact of Insulin-like Growth Factor-I on Migration, Proliferation and Akt-ERK Signaling in Early and Late-passages of Vascular Smooth Muscle Cells

et al. 2007

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“…Studies on liver and kidney fibrosis in the iNOS knock-out mouse, and our previous work in Peyronie's disease and its animal models, vaginal fibrosis, aging-related arterial media fibrosis, and in corporal fibrosis, suggests that despite iNOS may be initially induced during an early inflammatory process, its main role is as an antifibrotic agent. 12,13,[24][25][26][27][28][29]32,33,37,38,50 This may occur via cGMP produced by the nitric oxide from iNOS, and/or the nitric oxide can directly reduce collagen synthesis, myofibroblast formation in the interstitial connective tissue, and reactive oxygen species. 26,[30][31][32] In contrast to our study with vardenafil in the BCNR rat, the slight stimulation of iNOS induction by sildenafil in the BCNR animals was not significant.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16][17][18][19][20][21][22][23] The expression of iNOS in certain non-immunological tissues is assumed to be a defense mechanism against fibrosis. [24][25][26][27][28][29] The nitric oxide produced by iNOS, besides inhibiting collagen synthesis and the TGFb1 pathway, also quenches reactive oxygen species, and in some cases, the differentiation of fibroblasts to myofibroblasts, the cells that produce collagen in many fibrotic conditions. [30][31][32] In a recent study, we have shown that the PDE5 inhibitor, vardenafil, given for 45 days in the drinking water to rats subjected to bilateral cavernosal nerve resection (BCNR) [33][34][35] prevented the development of CVOD and the underlying SMC loss and fibrosis in the corpora cavernosa.…”

Section: Introductionmentioning

confidence: 99%

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

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It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal venoocclusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N ¼ 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg À1 day À1 ) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg À1 day À1 ) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.

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“…12 For this reason we included in the analysis the variable 'age' that was found to be directly related to the presence of CCAD (Figure 3) and ED. This analysis showed that age influenced significantly the PSV cut-off values.…”

Section: Discussionmentioning

confidence: 99%

Age-matched cavernous peak systolic velocity: a highly sensitive parameter in the diagnosis of arteriogenic erectile dysfunction

et al. 2005

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Recently it has been reported that there is a strict correlation between erectile dysfunction (ED) and cardiovascular diseases, but the importance of such relationship still needs to be addressed. Ultrasonographic peak systolic velocity (PSV), is considered a reliable parameter for the diagnosis of arteriogenic ED. However, the cut-off value of PSVo30 cm/s has sufficient sensitivity only in the diagnosis of advanced arteriogenic ED and it is not representative of peripheral vascular alterations. In the present study, we set up an age-adjustment of PSV -calculated with the formula PSV o6.73 þ age Â 0.7 -that permits a more accurate diagnosis of vascular aetiology in ED patients and may predict the presence of carotid wall alterations. We studied 179 consecutive subjects (mean age 52 years, range 23-79 years), with a history of ED of at least 6 months, by means of penile colour doppler ultrasonography (P-CDU) and common carotid arteries colour doppler ultrasonography (CCA-CDU) between June 2003 and September 2004. Statistical analysis was carried out with the statistical software R. PSV and CCAD values showed a statistically significant negative correlation. Age adjustment further improved this relationship permitting to identify an age-dependent PSV cutoff given by the formula PSV o6.73 þ age Â 0.7. The age-adjusted PSV cut-off allows an accurate interpretation of vascular aetiology in ED patients and predicts the presence of carotid wall alterations, from the intima-media pathologic thickness to the plaque formation, with high values of both sensitivity and specificity.

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Aging-related induction of inducible nitric oxide synthase is vasculo-protective to the arterial media

Abstract: These observations suggest that ED and arteriosclerosis in the aging male may share a common etiology, and that the expression of iNOS by the SMC is an attempt to counteract this fibrosis.

Cited by 86 publications

References 41 publications

Impact of Insulin-like Growth Factor-I on Migration, Proliferation and Akt-ERK Signaling in Early and Late-passages of Vascular Smooth Muscle Cells

Impact of Insulin-like Growth Factor-I on Migration, Proliferation and Akt-ERK Signaling in Early and Late-passages of Vascular Smooth Muscle Cells

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

Age-matched cavernous peak systolic velocity: a highly sensitive parameter in the diagnosis of arteriogenic erectile dysfunction

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