Biomedical subjects

M Osborne-Pellegrin

Publications and source records attributed to M Osborne-Pellegrin.

17 recordsLinked to original sources

PubMed2001

Endoluminal smooth muscle cell seeding limits intimal hyperplasia.

PURPOSE: Intimal hyperplasia is one of the main responses of the vascular wall to injury. In the current study, we tested the hypothesis that endoluminal seeding of host syngeneic vascular cells could limit intimal hyperplasia induced by either mechanical deendothelialization or chronic allograft rejection in rat aorta. METHODS: An experimental model of in situ seeding of syngeneic endothelial cells, smooth muscle cells (SMCs), and fibroblasts (FIBs) was used in mechanically deendothelialized and allografted aortas. In a preliminary study, the ability of the three cell types (n = 5 per group) to seed on the deendothelialized luminal surface of the aortic wall was evaluated after 2 days, with the use of fluorescent PKH as marker. In the first model, the abdominal aorta of Lewis rats was deendothelialized (n = 6) or deendothelialized and seeded with either SMCs (n = 6) or FIBs (n = 6) before flow was restored. In the allograft model, aortas were harvested from dark agouti rats and orthotopically grafted in Lewis receivers, directly (n = 6) or after deendothelialization. Deendothelialization was performed alone (n = 6) or associated with the seeding of similar host (Lewis) syngeneic SMCs (n = 6) or FIBs (n = 6). Results were evaluated at 2 months with histologic and morphometric methods. RESULTS: SMCs and FIBs were able to adhere in situ to the deendothelialized aortic wall, whereas endothelial cells were not. In mechanically deendothelialized aortas, the seeding of syngeneic SMCs led to a significant reduction in intimal thickness compared with deendothelialized aortas or FIB-seeded aortas (26.9 +/- 1.7 microm vs 55.5 +/- 1.7 and 56.7 +/- 1.7 microm, respectively), and a lower nuclear content (382.2 +/- 35.7 microm(2) vs 779.6 +/- 65.9 and 529.6 +/- 24.3 microm(2), respectively) of neointima. After SMC seeding, intimal hyperplasia was richer in elastin, whereas after FIB seeding it was richer in collagen. In allografts, the seeding of syngeneic SMC led to a significant reduction in intimal thickness compared with control aortas, deendothelialized aortas, or FIB-seeded aortas (31.6 +/- 1.1 microm vs 88.55 +/- 2.8, 74.6 +/- 2.9, and 85.7 +/- 2.6 microm, respectively), and a reduced nuclear content of the neointima (444.9 +/- 23.4 microm(2) vs 1529.1 +/- 116, 972.3 +/- 50, and 645.2 +/- 32.4 microm(2), respectively). Differences observed in the extracellular matrix composition were equivalent to those observed in the mechanically deendothelialized model. CONCLUSIONS: Our results suggest that endoluminal seeding of syngeneic SMCs can be effective in reducing intimal hyperplasia both in a deendothelialization model and in arterial allografts. SMC and FIB endoluminal seeding led to a significatively different accumulation of extracellular matrix in the intima.

Analysis of Variance↗

PubMed2001

Fenestrations of the carotid internal elastic lamina and structural adaptation in stroke-prone spontaneously hypertensive rats.

Our aim was to determine the structural factors that determine the mechanical adaptation of the carotid arterial wall in stroke-prone hypertensive rats (SHRSP). Distensibility-pressure and elastic modulus-stress curves assessed by in vivo echo-tracking measurements indicated a reduction in arterial stiffness in 13-week-old SHRSP compared with Wistar-Kyoto rats (WKY). Elastin and collagen contents determined biochemically were not different between SHRSP and WKY. Confocal microscopy showed that the mean area of fenestrations and fraction of area occupied by fenestrations of the internal elastic lamina (IEL) were smaller in SHRSP than in WKY, which indicated a reduction in stress-concentration effects within the IEL. Immunohistologic staining of EIIIA fibronectin isoform and total fibronectin (also as determined by Western blot) was greater in SHRSP, which suggested increased cell-matrix interactions. We suggest that these structural modifications of the vascular wall play a synergistic role in the mechanical adaptation to a high level of stress in SHRSP.

Animals↗

PubMed2001

Mechanical strength of the isolated carotid artery in SHR.

We have previously reported an adaptation of arterial wall elasticity in spontaneously hypertensive rats (SHR) that involves an increase in both fibronectin/alpha5beta1-integrin complexes and smooth-muscle elastic lamellae connections. We examined the mechanical strength (MS) of the carotid artery in relation to its elastic properties, its elastin/collagen content, and the structure of the internal elastic lamina. MS was defined as the in vitro intraluminal pressure and wall stress that produces rupture of the vascular wall. Intact carotid arteries from 3-month-old normotensive rats (Wistar-Kyoto, WKY) and SHR were cannulated on a specially designed device and adjusted to their in situ length. A slowly increasing static pressure was applied until wall rupture occurred to determine the static mechanical behavior and MS. Static elasticity was similar in SHR and WKY, as were the rupture pressure (2740+/-90 versus 2740+/-40 mm Hg) and wall stress at rupture (11.5+/-1.0 versus 12.8+/-0.4 MPa), indicating equivalent MS in both groups. Histological examination showed several wall ruptures and dissociation of lamellar units that did not differ significantly between the 2 groups. Confocal microscopy showed that the size of fenestrations of the internal elastic lamina and the fraction of area occupied by them were reduced 3-fold in SHR. We have demonstrated that static elasticity of the arterial wall and mechanical strength are similar in carotid arteries from SHR and WKY.

Animals↗

PubMed2001

[Regulation of elastin synthesis].

Elastin is the main protein of elastic fibers and confers the property of elastic recoil to the tissues such as arteries, lung, elastic cartilage,... Elastin synthesis goes through several steps: gene transcription, alternative splicing of pre-mRNA, mRNA translation, hydroxylation of some proline residues of the newly synthesized protein-tropoelastin-, association of with a 67 kDa chaperone protein, secretion of tropoelastin molecules in the extracellular space, and their deposition on the microfibrillar scaffold which contains fibrillin 1, fibrillin 2, MAGP 1 and MAGP 2,.... After the synthesis of cross-links-lysinonorleucine, desmosine, isodesmosine-, elastin becomes insoluble and elastic. The elastogenic pathway is regulated at many levels. The most recently described regulatory mechanism of elastin synthesis is the control of elastin mRNA stability. Elastogenesis is well controlled during development and aging but remains responsive to external factors such as soluble compounds-cytokines, vitamins, hormones,...- and hemodynamic stress. In order to ensure its function, both quantity and quality of elastin should be and should remain optimal in elastic tissues.

Alternative Splicing↗

PubMed2000

Heritability of intracerebral hemorrhagic lesions and cerebral aneurysms in the rat.

BACKGROUND AND PURPOSE: Under certain conditions, the Brown Norway (BN) rat is susceptible to intracerebral hemorrhagic vascular (ICV) lesions within the cerebral cortex, whereas the Long-Evans (LE) rat is prone to develop aneurysms in the circle of Willis. The incidence of these 2 pathological phenotypes was studied in progeny of different BNXLE crosses to determine their heritability in these new rat models. In addition, a possible link between ICV lesion occurrence and either the susceptibility to spontaneous rupture of the arterial internal elastic lamina (IEL) or basal plasma angiotensin-converting enzyme (ACE) activity was also studied in back-cross (BC) F1XBN rats, the only second-generation group with a high incidence of ICV lesions. METHODS: To induce cerebrovascular lesions, rats were submitted to experimental hypertension associated with ligation of 1 carotid artery. After death, the brain was examined for cerebral lesions. Numbers of arterial IEL ruptures were determined microscopically with the use of en face preparations. Plasma ACE activity was determined before the induction of hypertension. RESULTS: In general, groups that developed ICV lesions presented a low incidence of aneurysms. ICV lesion incidence was similar in F1 hybrids and BC(F1XBN) and greatly decreased in F2 and BC(F1XLE) rats compared with BN rats. No cerebral aneurysms developed in F1 rats. Aneurysmal incidence was 24% (20% ruptured) in LE, 42% (59% ruptured) in F2, and 50% (75% ruptured) in BC(F1XLE) rats. In BC(F1XBN) rats, neither the incidence of IEL rupture nor the plasma ACE activity was higher in the rats with ICV lesions. However, the mean blood pressure level was higher in these rats, and peak blood pressure was higher in rats with the most severe grades of ICV lesions. CONCLUSIONS: These data suggest a polygenic and dominant mode of inheritance of ICV pathology. The formation of aneurysms in the circle of Willis tended to be favored, and their rupture was clearly increased by the presence of BN rat alleles within the LE rat genome. These data may provide the basis for future studies to determine, in new rat models, which genes are involved in these pathologies.

Animals↗

PubMed1999

Influence of elastin gene polymorphism on the elastin content of the aorta: A study in 2 strains of rat.

The elastin content in the thoracic aorta of male Brown-Norway (BN) rats is 31.4+/-1.2% (dry weight), whereas that of male LOU rats is 37.2+/-1.0%. A similar difference in the elastin content of the thoracic aorta is also observed in female animals. Furthermore, in the thoracic aorta of young, growing rats as well as in cultured aortic smooth muscle cells, the steady-state level of elastin mRNA is significantly lower in the BN than in the LOU strain. These results suggested that 1 or more genes control the elastin mRNA level and the elastin content in the aortas of BN and LOU rats. A possible relationship between a polymorphism in the elastin gene and the elastin content of the aorta was tested. For this purpose, the aortic elastin content was measured in F(1) and F(2) generations bred from LOU and BN rats and was compared with that of the F(0) (parental) generation. A polymorphic marker located in intron 25 of the elastin gene has been used to genotype the F(2) rats. The degree of genetic determination of aortic elastin content was estimated to be 73% in the F(2) cohort, but the elastin locus accounts for only 3. 9% of the total variance in aortic elastin content. Other genes are thus responsible for the major part of the observed interstrain difference by regulating the transcription of the gene, the stability of elastin mRNA, and/or posttranslational events.

Alleles↗

PubMed1997

Genetic susceptibility to experimental cerebral aneurysm formation in the rat.

BACKGROUND AND PURPOSE: The susceptibility to experimental cerebral aneurysm formation in arteries of the circle of Willis was studied in four strains of rats presenting different susceptibilities to the spontaneous rupture of the internal elastic lamina in extracerebral arteries: Brown-Norway (BN) > Wistar > Long-Evans (LE) > LOU. METHODS: Rats (150 g body weight) of the four strains were subjected to hypertension and a change in local cerebral blood flow by ligation of one common carotid artery for about 7 months. Six-month-old BN and LE rats were subjected to carotid ligation only for 11 to 13.5 months and treated or not (from 3 to 7 months of age) with an inhibitor of connective tissue fiber maturation, beta-aminopropionitrile (BAPN). RESULTS: Aneurysmal structures (AS) occurred mainly in the anterior cerebral/anterior communicating arterial complex and proximal part of the posterior artery. In hypertensive rats, the AS incidence was LE, 56%; Wistar, 33%; BN, 17%; and LOU, 11%. When normotensive and subjected to carotid ligation only, LE rats showed an even greater susceptibility to AS formation (86%) than BN (7%). BAPN treatment did not influence AS formation: LE (60%) versus BN (8%). CONCLUSIONS: These results suggest that genetic factors are involved in cerebral aneurysm formation in the rat. The susceptibility of the internal elastic lamina of extracerebral arteries to spontaneous rupture does not appear to be a determinant genetic trait in the propensity to develop aneurysms in arteries of the circle of Willis. The comparison of these different rat strains may be very useful for studying factors contributing to cerebral aneurysm pathogenesis.

Aminopropionitrile↗

PubMed1996

Presensitization accelerates allograft arteriosclerosis.

Transplant arteriosclerosis is the major factor influencing allograft survival after the first year posttransplantation. The host's immunologic response is one of the principal effectors responsible for the constitution of this vascular wall lesion, but the effector pathway and the factors influencing the immune injury are not clear. In a rat abdominal aortic allograft model, we used a skin priming method to study the influence of sensitization on the occurrence of vascular wall lesions. Primed rats developed transplant arteriosclerosis lesions involving medial decellularization and intimal proliferation before the 21st day, whereas naive animals had the same lesions at 2 months posttransplantation. A significant difference between primed and naive rats was found for medial thickness (48.00 +/- 2.85 microm versus 79.34 +/- 2.55 microm, P<0.001) and smooth muscle cell content (160 +/- 28 cell/mm versus 466 +/- 19 cell/mm, P<0.001) at 21 days posttransplantation, and intimal hyperplasia was seen in primed animals at that time, whereas it was not observed in naive rats until the 60th day. The immune profile in naive and primed animals was different. The immune cells infiltrating the arterial wall in naive rats, were principally macrophages and CD8+ T-lymphocytes. No Ig or complement deposition was detected. IgG and complement activated fraction were present in the media of primed animals as early as the fifth day posttransplantation and CD4+ T lymphocytes were the dominant immune cell population. In conclusion, sensitization influences the immune mechanisms responsible for the development of transplant arteriosclerosis and alters the rate of its evolution.

Animals↗

PubMed1996

Effect of defective connective tissue on the formation of aneurysmal-like structures in the rat testicular artery.

Microscopic aneurysmal-like structures (ALS) develop spontaneously in the convoluted rat testicular artery and have been previously proposed as a model relevant to cerebral aneurysms. The effect of defects in connective tissue fibres on ALS formation was investigated by microscopy using two approaches: (i) the study of the effect of beta-aminopropionitrile (BAPN), an inhibitor of the cross-linking of elastic and collagen fibres, on the incidence, size and morphology of ALS in spontaneously hypertensive rats (SHR) and their normotensive controls (WKY). The straight spermatic artery was studied for comparison. (ii) The determination of the incidence of spontaneous ALS in Brown Norway (BN) and Long Evans (LE) rats which are highly susceptible (BN) or resistant (LE) to the spontaneous rupture of the arterial internal elastic lamina. (i) BAPN increased the number and size of ALS in SHR and WKY rats and had no effect on the straight spermatic artery and (ii) ALS were more numerous and of greater size in BN than in LE rats. Taken together, these results show that defective connective tissue fibres may favour the formation and induce the enlargement of aneurysmal-like structures. By analogy, these data suggest that a lack of connective tissue fibre integrity may be of importance in cerebral aneurysm formation and development.

Aminopropionitrile↗

PubMed1992

The rat testicular artery: a model of spontaneous aneurysmal-like structure formation.

The straight spermatic and highly convoluted testicular arteries were studied by light microscopy in adult and aging normotensive (NT) and spontaneously hypertensive (SHR) rats. In younger rats, on the internal part of bends of the testicular artery, areas lacking the media similar to classical cerebral arterial medial defects were observed. At the same location, in other bends, structurally defective areas (SDA) constituted by or including medial defects but also lacking the internal elastic lamina and which in some cases evaginated, were present. Structurally defective areas were less numerous in SHR than in NT rats at 6 months, suggesting that intrinsic differences may exist between rat strains. In contrast, in old rats, the number of SDA was higher in hypertensive than in normotensive rats, supporting the role of hemodynamics in SDA formation. With age, SDA enlarged in both rat strains, and most of them became structurally similar to aneurysms, ie, lacking the internal elastic lamina and medial cells and with a dilated lumen, supporting the view that medial defects are sites of aneurysmal structure development. In hypertensive rats, fibrin and lipid deposits occurred within these aneurysmal-like structures. In the straight part of the spermatic artery no such structural modifications occurred, suggesting that either hemodynamics and/or structural development, both dependent on arterial geometry, are determinant in SDA formation. The results are discussed in view of the use of the rat testicular artery as a possible model of the formation of spontaneous aneurysmal-like structures relevant to cerebral aneurysms.

Aging↗

PubMed1992

Arterial hypertension and aneurysmal dilatation.

Hemodynamic parameters and especially systemic hypertension are considered to be significant factors in the progression of aortic aneurysmal dilatation. We have recently described an original experimental model of aortic aneurysm induced by transparietal infusion of elastase in the rat abdominal aorta. In order to evaluate the effect of hypertension on the aneurysmal remodeling of the arterial wall induced by perfusion of elastase activity, this experimental model was applied to renovascular hypertensive (N = 17), spontaneously hypertensive (N = 18) and normotensive rats (N = 17). The aneurysms were induced by infusion of 15 units of hog pancreatic elastase of a one centimeter isolated aortic segment in anesthetized rats which were sacrificed two weeks later. The aneurysmal length and diameter were measured in vivo using a micrometer in a surgical microscope. The aortas were then fixed in formalin and embedded in paraffin for standard histological study. The animals which died during the experimental period were examined. All rats presented a macroscopic aneurysm two weeks after the infusion of elastase. Histologically, the aneurysmal area was characterized by the disappearance of the normal elastic network and by the presence of a collagenic wall. The dimensions of the aneurysms (transversal diameter and length) were greater in hypertensive than in normotensive animals (F = 11, P less than 0.001) and aneurysmal dimensions were positively correlated with the level of blood pressure (r = 0.56, P less than 0.001). Moreover, the frequency of aortic rupture was greater in renovascular hypertensive (4/17) than in spontaneously hypertensive (1/18) and normotensive (0/17) rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Rupture of the internal elastic lamina and vascular fragility in stroke-prone spontaneously hypertensive rats.

We studied a possible relation between stroke and an enhanced susceptibility to rupture of the arterial internal elastic lamina by comparing stroke-prone spontaneously hypertensive rats with spontaneously hypertensive rats, which have a very low incidence of stroke. We quantified interruptions in the internal elastic lamina in certain arteries and studied the effect of beta-aminopropionitrile, an inhibitor of cross-link formation in collagen and elastic fibers, on rupture of the internal elastic lamina and on mortality in these two substrains. To eliminate any influence of higher blood pressure in the stroke-prone rats on the parameters studied, we used antihypertensive treatment to obtain equivalent blood pressures in the two substrains. Results showed that stroke sensitivity was associated with an enhanced early spontaneous rupture of the internal elastic lamina in the caudal artery, an increased susceptibility to beta-aminopropionitrile-induced rupture of the internal elastic lamina, and earlier mortality, mainly from aortic rupture, under beta-aminopropionitrile treatment. These findings suggest that stroke-prone rats have an enhanced minor connective tissue defect that is expressed by rupture of the internal elastic lamina and may be related, at least in part, to their greater vascular fragility and increased susceptibility to stroke.

Animals↗

PubMed1987

[Formation of disruptions of the internal elastica lamina, spontaneous and BAPN induced, in arteries of stroke-prone spontaneously hypertensive rats].

In the caudal and renal arteries of the male Wistar rat, interruptions in the internal elastic lamina (IEL) form spontaneously with age. beta-aminopropionitrile (BAPN), which is an inhibitor of the enzyme lysyl oxidase implicated in the synthesis of elastin, is able to induce in the young Wistar rat interruptions in the IEL which are morphologically very similar to those which form spontaneously. The spontaneously hypertensive strain (SHR), together with the Stroke-Prone spontaneously hypertensive substrain (SHR-SP) which is susceptible to cerebrovascular accidents early in life, have been selected from the Wistar strain. We have compared the incidence of IEL interruptions in caudal and renal arteries from SHR-SP aged 12 and 23 weeks with that observed in age-matched SHR. In addition, we have studied the effect of BAPN, administered from weaning during two weeks, on the formation of interruptions in the IEL in the caudal artery of SHR-SP, SHR and normotensive Wistar and WKY rats. Interruptions in the IEL were quantified by light microscopy on longitudinal semi-thin sections. Results showed that, in the caudal and renal arteries of SHR-SP, the number of interruptions in the IEL which form spontaneously was greater than in SHR. Moreover, BAPN administered between the age of 3 and 5 weeks led to the premature formation of a higher level of interruptions in the IEL in SHR-SP than in the 3 other strains of rat. The SHR was the strain which developed the least.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1986

[Absence of in vivo binding of deoxyribonucleic acid to the glomerular basement membrane in C57BL/6 mice].

The intraaortic injection of radiolabeled deoxyribonucleic acid (DNA) into C57BL/6 mice treated with bacterial lipopolysaccharides 48 hrs. before, induced the renal deposition of DNA, as previously reported. Autoradiographic studies of the kidneys obtained from such mice did not demonstrate a selective binding of radiolabeled DNA to the glomerular basal membrane. These results argue against the in situ formation of DNA:anti-DNA immune complexes which is a proposed mechanism in the development of tissue lesions in the course of systemic lupus erythematosus.

Animals↗

PubMed1980

Intimal lesions in rat caudal artery. Ablation, replacement, and receptor studies on the protective effects of estrogen.

The incidence of spontaneous lesions of the intima in the rat caudal artery is significantly higher in male than in female Wistar rats at 12 weeks of age. After gonadectomy at 5 weeks, lesions in both sexes at 12 weeks reach a level intermediate between those seen in age-matched intact males and females. After gonadectomy at 5 weeks, lesions in both male and female rats are unaffected by testosterone administration but are reduced to below female control levels by diethylstilbestrol. In contrast, diethylstilbestrol administration does not significantly reudce lesion incidence in intact male rats. Binding studies provided no evidence of estrogen-binding sites in cytosol from caudal arteries, but heart and kidney cytosols from both male and female rats contain a single class of high affinity (10(-10)M) binding sites with specificity characteristic of estrogen receptors. Longitudinal studies (4-11 weeks of age) provided no evidence for a change in receptor profile as a factor contributing to the increased lesion incidence in mature male rats.

Animals↗

PubMedDate not supplied

Endovascular grafting in elastase-induced experimental aortic aneurysms in dogs: feasibility and preliminary results.

PURPOSE: A new model of aortic aneurysm was developed in 12 beagles to study the feasibility of endoluminal exclusion of aortic aneurysms. MATERIALS AND METHODS: After preliminary experiments in four dogs, aneurysms were induced by infusing elastase into an isolated segment of the abdominal aorta in eight dogs. To create aortic endoprostheses, a Palmaz stent was sutured onto each end of an ultrathin Dacron tube. Endoprosthesis placement was performed under fluoroscopic and intravascular ultrasonographic (US) guidance. The endoprostheses were introduced via a femoral arteriotomy, through a 12-F sheath positioned in the aorta, and then were expanded on an angioplasty catheter. RESULTS: Intravascular US and aortography showed aneurysms in the elastase-perfused area in the eight animals and demonstrated the exclusion of the aneurysm by the endoprostheses in six cases. Intravascular US was more accurate than aortography in demonstrating two cases of endoprosthesis dysfunction. Aneurysm formation was proportional to the loss of elastic tissue observed at histologic examination of the elastase-infused area. Macro- and microscopic examinations confirmed thrombosis of the excluded part of the aneurysm and patency of all grafts. CONCLUSION: This model and intravascular US appear helpful in exploring the feasibility of endovascular treatment of abdominal aortic aneurysm.

Animals↗

PubMedDate not supplied

Aortic elastin and collagen content and synthesis in two strains of rats with different susceptibilities to rupture of the internal elastic lamina.

We have previously characterized two normotensive strains of rats which differ markedly in their susceptibility to spontaneous rupture of the internal elastic lamina (IEL), the Brown Norway (BN) being very susceptible and the Long Evans (LE) being resistant. Here we quantified biochemically the elastin and collagen content of aortae from adult male BN and LE rats aged 12, 18 and 22 weeks and showed that the elastin content was lower and the collagen content higher in the BN strain than in the LE strain, resulting in a markedly lower elastin/collagen ratio in the former strain. These modifications were present both in the thoracic aorta, which is devoid of IEL ruptures, and in the abdominal segment where ruptures frequently occur in the BN rat, suggesting that they could represent a predisposing factor in the presence of other local factors. Quantifications of relevant mRNAs in aortae of younger male BN and LE rats by Northern blot showed that there are lower tropoelastin transcript levels in the BN rat at 6 weeks in both thoracic and abdominal segments than in the age-matched LE rat. In contrast there was no consistent interstrain difference in alpha 1 type I collagen transcripts and alpha 1 type III collagen transcripts were higher in the BN aorta only at 6 weeks in the abdominal segment. We conclude that the BN rat presents an aortic elastin deficit which appears to be in part explained by a decreased elastin synthesis in young, growing rats and may be genetically determined. However, a direct relation of this elastin deficit with susceptibility to rupture of the IEL cannot be concluded from this study.

Animals↗