Complete Loss of Functional Smooth Muscle Cells Precedes Vascular Remodeling in Rat Aorta Allografts

Bigaud, Marc; Schraa, E. O.; Andriambeloson, Emile; Lobstein, Valerie; Pally, Charles; Kobel, Tanja; Berthou, Christian; Zerwes, Hans-G nter

doi:10.1097/00007890-199912150-00013

Cited by 21 publications

(28 citation statements)

References 22 publications

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“…In addition, we recently reported that while the rat aortic allografts fully preserved their main function of blood conductance, they completely lose their functional EC and SMCs within 2-3 weeks, indicating an acute vascular rejection preceding graft vascular remodelling (5,6,11). To what extent these functional/histopathological changes mirror those that may develop in solid-organ transplants remains to be established.…”

Section: Discussionmentioning

confidence: 98%

“…One issue concerns the fact that the severe elastica lamina destruction, medial SMC necrosis and prominent cellular inflammatory response seen in rat aortic allografts are unlikely to be observed in chronically rejecting human explants or autopsy specimens (18)(19)(20). Another point of concern is the fact that vessels of human solid organ grafts developing morphological evidences of CGA still have functional vascular SMCs able to dilate or constrict in response to pharmacological agents (21,22), whereas rat aorta allografts become rapidly nonfunctional vessel conduits far before any CGA formation (5,6,11). These observations, together with the present study demonstrating that the main renal artery, and most probably a major part of intrarenal arteries of kidney allografts as well, preserve their muscular function up to 33 weeks post-Tx, when intimal thickening becomes apparent and grafts start failing, suggest that arteries of rat kidney allografts could be considered as a more relevant model than rat aorta allografts to study the pathophysiology of CGA.…”

Section: Discussionmentioning

confidence: 99%

“…When the constriction reached the steady state, acetylcholine (Ach, 10 lm) was added to the bath in order to assess the EC-dependent vasorelaxation. It was previously shown that, at the concentrations used, the effects of Phe and Ach correspond to their maximal effect (Emax) (5,6).…”

Section: Ex Vivo Monitoring Of Vessel Allografts Functionmentioning

confidence: 95%

“…As in such models histological assessment is limited in its ability to provide quantitative data, or to identify physiological events that may be relevant for the understanding of CGA processes, we have previously developed an ex-vivo assay to monitor post-Tx changes in the graft vasculature function of rat abdominal aorta transplants (5,6). We have demonstrated that functional endothelial cells (ECs) and smooth muscle cells (SMCs) of rat aortic allografts are lost before any manifestation of intimal proliferation, suggesting an acute rejection of the vascular wall preceding the development of CGA (5,6). However, it remains controversial as to what extent the vascular changes seen in aortic allografts represent those that develop in solid-organ transplants.…”

Section: Introductionmentioning

confidence: 99%

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Transplantation Induced Functional/Morphological Changes in Rat Aorta Allografts Differ from Those in Arteries of Rat Kidney Allografts

Andriambeloson

Cannet

Pally

et al. 2004

American Journal of Transplantation

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The functional/morphological changes observed in rat aorta allografts were compared with those seen in the arteries of rat kidney allografts.Untreated allografts (F344-to-LEW) were collected at various times post-transplantation (Tx). Vascular smooth muscle cell (SMC) constriction to phenylephrine (Phe) and endothelial cell (EC)-dependent relaxation to acetylcholine (Ach) were assessed. Neointima formation in graft vessels was assessed by histology.In aorta allografts, the effects of Phe and Ach were irreversibly abolished within 3-2 weeks post-Tx. Neointima formation was consistently detected between 4 and 8 weeks post-Tx.In kidney allografts, sign of vasculopathy was seen in 10, 30 and 40% of resistance arteries at 8, 16 and 33 weeks post-Tx, respectively. In the main renal artery, substantial neointima formation was not apparent before 33 weeks post-Tx, the vasoconstrictor effect of Phe was fully maintained until then, and Achinduced vasorelaxation was irreversibly reduced by approximately 70% from week 2 post-Tx onwards.These results indicate that the post-Tx functional/ morphological changes seen in aorta allografts do not reflect those seen in arteries of kidney allografts. Hence, renal arteries from rat kidney allografts can be considered as a more relevant model to study the cascade of events leading to Tx-induced CGA in solid organ allografts.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Ex Vivo Monitoring Of Vessel Allografts Functionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transplantation Induced Functional/Morphological Changes in Rat Aorta Allografts Differ from Those in Arteries of Rat Kidney Allografts

Andriambeloson

Cannet

Pally

et al. 2004

American Journal of Transplantation

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“…In a recent study, we showed that although rat aortic allografts maintain their function of blood conductance for weeks after Tx, they lose their functional smooth muscle cells (SMCs) within 14 days after Tx, suggesting an acute rejection of SMCs occurring before any visible signs of vascular remodeling (not seen before 4 weeks after Tx). 11 To our knowledge, graft endothelial dysfunction has not been assessed in rodent models of Tx as yet. Therefore, in the present study, we focused our attention on the functional and morphological consequences of Tx on the graft endothelium.…”

mentioning

confidence: 99%

Endothelial Dysfunction and Denudation in Rat Aortic Allografts

Andriambeloson

Bigaud

Schraa

et al. 2001

ATVB

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Abstract-Clinical evidence suggests that early endothelial cell (EC) dysfunction may predict the development of graft vascular disease. We wished to assess the early functional and morphological changes in the graft endothelium in a commonly used animal model of graft vascular disease, the rat aortic interposition allograft model. To assess graft EC function, regulation of vascular tone by ECs was monitored in aortic rings from grafts harvested at various times after transplantation (Tx). EC morphology was assessed by silver staining, which was followed by en face inspection of the luminal side of the grafts. Acetylcholine-induced EC-dependent vasorelaxation was reduced in allografts at post-Tx days 7 and 14, whereas in syngeneic grafts EC-dependent relaxation was unaffected at any time after Tx. In separate grafts collected at the same time points, massive leukocyte adhesion at post-Tx day 7 and EC denudation at days 14 and 28 were evident in allografts but not in syngeneic grafts. At post-Tx day 56 (a time at which vessel wall remodeling is pronounced in this model), an intact EC layer covered the grafts. EC dysfunction and morphological changes were prevented by immunosuppression of recipient rats with cyclosporine. Our study shows that Tx-induced EC dysfunction in rat aortic allografts can be observed within 1 week of Tx in rat aortic allografts and that this is occurring concomitantly with enhanced leukocyte adhesion to the graft ECs. These changes occur before any other morphological or functional changes described thus far in this model and appear to be immune-driven. Taken together, these results show that Tx-induced early EC dysfunction, as described in patients, may be studied in the model of rat aortic Tx. Key Words: endothelium Ⅲ vasorelaxation Ⅲ graft Ⅲ rejection Ⅲ aorta T he development of graft vascular disease (GVD) is a leading cause of long-term graft failure. GVD is mainly characterized by the accelerated development of concentric atherosclerotic lesions in arteries of solid organ grafts, leading to impaired blood perfusion and functional deterioration (see reviews 1,2 ). Although the exact pathogenesis of GVD remains to be established, several lines of evidence suggest that it may be initiated by an early injury at the level of the graft endothelial cells (ECs), 3,4 inasmuch as these cells are the first donor cells to be encountered by recipient leukocytes. Supportive evidence is provided by a clinical study demonstrating that early endothelial dysfunction, seen within 15 days after transplantation (Tx), predicts the development of intravascular ultrasound-detectable Tx coronary artery disease at 1 year after heart Tx. 5 In addition, the degree of early activation of arterial/arteriolar endothelium, as defined by intercellular adhesion molecule-1 or human leukocyte antigen-DR expression, predicts the rate of development of coronary artery disease and the risks of graft failure. 6 In the present study, we wished to assess the function of graft endothelium at early post-Tx time points and to mo...

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