| BackgroundPathologic studies in animals and human have clearly demonstrated that proliferation of adventitial vasa vasorum was associated with progression of coronary atherosclerosis. The density of newly formed vasa vasorum was found to parallel the severity of de novo atherosclerotic disease and increased adventitial neovascularization were observed at the site of intimal hyperplasia in animal models of arterial angioplasty and stenting. However, the exact mechanisms of adventitial angiogenesis in atherosclerosis remain unclear.It is well known that lymphatic vessels, which commonly accompany blood vessels in tissues, drain extravasated bloodless fluid, protein, and inflammatory cells from the tissues and take an active part in inflammatory diseases. Recent studies have reported that lymphatic vessels were enlarged in chronic inflammatory skin diseases and rejected kidney transplants contained abundant lymphatic vessels. Lately it was found that lymphangiogenesis prevented mucosal edema and these neogenetic lymphatic vessels persisted in chronic airway inflammation. Although the presence of adventitial inflammatory infiltration in close proximity to intimal atherosclerotic plaques has been recognized for more than 4 decades, the clinical relevance of this finding was not clear until quite recently when inflammatory infiltration was proved to be present in adventitia after coronary balloon injury. Inflammatory cells like macrophages can secret cytokines and growth factors to promote angiogenesis and lymphangiogenesis. However, the relationship between adventitial lymphangiogenesis and intimal hyperplasia are still unknown. In the present study we tested the hypothesis that adventitial angiogenesis and lymphangiogenesis are initially induced by intimal inflammation after endothelial injury and these neogenetic vessels in turn promote intimal inflammation and neointimal hyperplasia by transportation and activation of inflammatory cells. Aims1. To observe angiogenesis and lymphangiogenesis after balloon injury in rat aortic artery.2. To probe the correlation between neointimal hyperplasia and angiogenesis and lymphangiogenesis.3. To explore the role of inflammatory cells in the process of angiogenesis and lymphangiogenesis in adventitia after balloon injury.4. To detect the change of VEGF-A, VEGF-C and PDGF-B in aortic wall after balloon injury and clarify their regulatory mechanism in angiogenesis and lymphangiogenesis.5. To investigate the possible mechanism of adventitial angiogenesis and lymphangiogenesis in promotion of atherosclerosis and neointimal hyperplasia.Methods1. Animal modelSixty male Wistar rats which were successfully underwent balloon-induced aortic endothelial injury and divided randomly into 6 groups with 10 rats in each group, while 10 rats received only sham operation and served as a control group. Rats were housed under conditions of constant room temperature (22℃) and a 12 h dark/12 h light cycle, and fed a standard diet. All rats underwent anesthesia with intraperitoneal injection of pentobarbital (30mg.kg-1) and the left external carotid artery was exposed to introduce a 2F embolectomy catheter (Baxter Healthcare Corp., Irvine, CA, USA) into the distal abdominal aorta. The balloon catheter was then inflated with saline and went back and forth in the abdominal aorta for 3 times to induce endothelial injury in group 1 to group 6 rats. Sham operation was performed in group 7 rats that underwent the same catheterization procedure but without balloon inflation. Groups 1 to group 6 rats were euthanized by intraperitoneal injection of a lethal dose of phenobarbitone on day 1, 3, 7, 14, 28 and 90 after the procedure, respectively, and group 7 rats were euthanized on day 1 after sham operation. After the abdominal aorta was harvested, aortic segments were snap-frozen in liquid nitrogen and stored at -80℃ for quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis, or fixed with 4% phosphate-buffered formaldehyde for 24 h for immunohistochemical and morphometric analysis.2. Morphometric analysisAortic segments were embedded in paraffin and cut into 6um thick sections which were stained with hematoxylin and eosin and analyzed using a computer-assisted morphometric analysis system (Image-Pro Plus 5) with particular attention to the intimal and the medial thickness. Vascular area within the external elastic lamina (EELA) and the internal elastic lamina (IELA) as well as the lumen area (LA) were measured. The I/M ratio was calculated as: I/M = (IELA- LA)/ (EELA - IELA). All parameters were measured from 3 sections selected from the proximal, the middle and the distal portion of the aortic segment and the values averaged.3. AntibodiesThe primary antibodies used were as follows: goat polyclonal antibody against human CD34 (1:200; Santa Cruz, CA. USA) to identify the blood endothelial cells; rabbit polyclonal antibody against human LYVE-1 (1:100; Santa Cruz, CA.) to tag lymphatic endothelial cells; rabbit polyclonal antibody against human CD68 (1:400; Santa Cruz, CA.) to mark macrophages; mouse monoclonal anti-a-SMA antibody( 1:2000; ab7817, Abeam) to label VSMC; rabbit polyclonal antibody against mouse VEGF-A (1:50; Santa Cruz, CA.); rabbit polyclonal antibody against human VEGF-C (1:50; Santa Cruz, CA.) and rabbit polyclonal antibody against PDGF-BB (1:100; ab15499, Abeam.). Second antibodies against IgG in rabbits, mice and goats were used.4. ImmunohistochemistrySections were deparaffinized and incubated with 5% goat serum or 5% BSA for 20 minutes to minimize the nonspecific binding to the primary antibody and incubated with the primary antibodies overnight at 4℃ in a moisture chamber. The sections were then incubated with the appropriate secondary antibody for 30 minutes at room temperature. To inhibit any endogenous peroxidase activity, the sections were incubated with 0.3% H2O2 in absolute methanol for 30 minutes. A peroxidase substrate solution containing 0.02% H2O2 and 0.1% 3, 3'-diaminobenzidine tetrahydrochloride (ZSBIO, China) in PBS was applied to display the reaction product with a brown color and the sections were then counterstained with hematoxylin. Incubation with PBS instead of the primary antibody was used as a negative control.5. Quantification of Adventitial angiogenesis and lymphangiogenesisThe total number of microvessels (CD34+) or lymph vessels (LYVE-1+) in the whole adventitia was counted under a light microscope at a high power magnification (×400). Vascular and lymph vessels were identified as morphologically circumferential brown products formed by one or more stained endothelial cells with at least one counterstained nucleus. In this case, a single brown dot was not counted. The number of adventitial microvessels (Ad-MV) and adventitial lymphatic vessels (Ad-LV) from 3 sections were counted and the mean values derived. All counting were performed by 2 independent investigators and the values were averaged.6. Real-time RT-PCRTotal RNA was extracted from the aortic tissue by Trizol (Invitrogen, Carlsbad, CA, USA) following the protocols recommended by the manufacturers. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed following the protocol recommended by the manufacturer. In brief, lug of RNA in 20ul of volume was reversely transcribed with oligo (dT) primer using M-MLV Reverse Transcriptase System (Promega, Madison, USA). The relative quantification of target genes was determined using the LightCycler (Roche Applied Science, USA) following the manufacture's protocol. The real-time quantitative polymerase chain reaction (real-time PCR) analysis for mRNA expressions in the aortic tissue was performed using a TaqMan probe method. The conditions for real-time PCR were as follows: denaturation at 95℃ for 30s, and in the following 50 cycles, denaturation at 95℃ for 0s, annealing for 10s and extension at 72 ℃ for 10s. Primer and probe sequence, PCR product size, annealing temperature and GenBank Access Number for each primer are listed in Tablel. Target gene expressions were calculated using 2△△Ct method and expressed as N-fold difference between experimental groups (group 1 to group 6) and control group (group 7) after normalizing to reference gene expressions.7. Statistical analysisData analysis was conducted using a statistical software package (SPSS 11.5, Chicago, USA). All measurements were expressed as mean ± SD. One-way ANOVA analysis was used to compare the differences among 7 groups. The correlation between the number of adventitial microvessels and lymph vessels and the I/M ratio was tested using simple (Pearson's correlation) and multiple linear regression analysis. P<0.05 was considered statistically significant.Results1. Neointima hyperplasia after balloon injuryThe aortic intima appeared as a single cell layer, the internal elastic lamina was intact and the external elastic lamina was in close contact with the adventitia in the control group of rats. Hyperplastic intima consisting of multiple layers of vascular smooth muscle cells (VSMC) and macrophages became evident on day 7 after balloon intervention and these changes reached a maximal level on day 28. The I/M ratio increased significantly on day 28 compared with that on day 7 after balloon injury (0.56±0.06, vs.0.17±0.02, P<0.001). However, this ratio did not show any further increase on day 90 compared with that on day 28 after balloon intervention (0.55±0.06 vs. 0.56±0.06, P>0.05 ).2. Adventitial angiogenesis after balloon injuryThe value of Ad-MV began to increase significantly on day 3 after balloon injury when compared with that in the control group (12.40±1.43 vs.7.80±1.32, P<0.001), and this difference became even greater on day 7 and day 14 (19.80±2.74 vs. 7.80±1.32, P<0.001 and 24.20±2.15 vs.7.80±1.32, P<0.001) after balloon intervention. However, the value of Ad-MV reached a plateau thereafter and did not show any further increase on day 28 and day 90 after balloon injury when compared with that on day 14 ((24.00±1.49 and 23.90±1.10 vs. 24.20±2.15, all P>0.05).3. Adventitial lymphangiogenesis after balloon injurySimilar to the change of Ad-LV, the value of Ad-LV began to rise on day 3 (6.4±1.1 vs. 2.5±0.53, P<0.001), continued to ascend on day 7(12.5±1.4 vs. 2.5±0.53, P<0.001) until a plateau was reached on day 14 (12.8±1.0 vs. 2.5±0.53, P<0.001) when compared with that in the control group. Thereafter the value of Ad-LV remained at a high level on day 28 (12.8±1.4 vs. 12.8±1.0, P>0.05,) and day 90 (12.6±1.3 vs. 12.8±1.0, P>0.05) after balloon intervention when compared with that on day 14.4. Macrophages distribution in the aortic wallImmunohistochemical staining using anti-macrophage antibody (CD68) revealed that CD68-positive cells were predominantly located in the adventitia near external elastic membrane on day 3, and scattered in the neointima and adventitia on day 7 and 14. Thereafter, CD68-positive cells were mainly present in adventitia on day 28. The percentage of macrophage number to total cell number in adventitia (macrophage index) was calculated. The results demonstrated that the macrophage index increased on day 3 (4.5%±0.8% vs. 0.6%±0.2%, P<0.001), peaked on day 14 (12.5%±1.3% vs. 0.6%±0.2%, P<0.001), maintained this level on day 28 (12.3%%±1.5%% vs. 0.6%±0.2%, P<0.001) when compared with that in the control group, and returned to the control level on day 90 after balloon injury.5. VEGF-A, VEGF-C and PDGF-B expressions in the aortic wall Immunohistochemical staining revealed that VEGF-A positive expressions werebarely visible while VEGF-C and PDGF-B expressions were not present in the control group. On the other hand, intensive VEGF-A expressions were evident in VSMCs and macrophages in the aortic wall on day 3, day 7 and day 14 after balloon injury. Thereafter, the intensity of VEGF-A expression diminished and only faint positive expressions were visible in these cells on day 90 after balloon intervention. VEGF-C positive expressions were mainly present in macrophages on day 7 and day 14 in neointima, appeared only in macrophages in the aortic adventitia on day 28 and became invisible on day 90 after balloon injury. PDGF-B positive expressions were mainly found in VSMCs and endothelial cells on day 3 and day 7, and went undetectable thereafter.6. mRNA expressions of VEGF-A and VEGFR-1The mRNA expression of VEGF-A started to increase as early as on day 1 after balloon injury, reached the peak level (approximately 14 fold of the control level) on day 3, declined on day 7 and reverted to the baseline level on day 28 after balloon intervention. The pattern of mRNA expressions of VEGFR-1 was similar to that of VEGF-A.7. mRNA expressions of VEGF-C and VEGFR-3The mRNA expression level of VEGF-C began to ascend on day 3, reached its plateau (approximately 12 fold of the control level) on day 7, remained unchanged until day 14, descended on day 28 and returned to the baseline level on day 90 after balloon intervention. The mRNA expression level of VEGFR-3 started to increase on day 7 and peaked (approximately 13 fold of control group's level) on day 14, decreased slightly on day 28 and reverted to the baseline level on day 90 after balloon injury.8. mRNA expressions of PDGF-B and PDGFR-βThe mRNA expression level of PDGF-B was up-regulated as early as on day 1, peaked (approximately 16 fold of the control level) on day 3, declined on day 7 and resumed its baseline level on day 14 after balloon injury. The mRNA expression of PDGFR-β also became up-regulated on day 1, reached its summit (approximately 11 fold of the control level) on day 7, decreased on day 14 and returned to the baseline level on day 28 after balloon intervention.9. Relationship between adventitial angiogenesis and lymphangiogenesis, and neointima hyperplasiaThere were significant correlations between the macrophage index and the I/M ratio on day 7, day 14 and day 28 (r=0.87, P=0.001, r=0.79, P=0.006 and r=0.68, P=0.03, respectively) with the highest correlation being found on day 7 after balloon intervention. However, such a correlation became insignificant on day 90 after balloon injury.Ad-MV showed significant correlations with I/M ratio on day 14, day 28 and day 90 (r=0.68, P=0.03, r=0.67, P=0.032 and r=0.81, P=0.004 respectively) with the highest correlation being found on day 90 after balloon intervention. Similarly, significant correlations were found between Ad-LV and I/M ratio on day 14, day 28 and day 90 (r=0.78, P=0.007, r=0.75, P=0.013, and r=0.79, P=0.006, respectively) with the highest correlation being found on day 90 after balloon injury. Ad-MV and Ad-LV were independent factors of neointima hyperplasia (R2=0.89, P=0.000). Conclusions1. Adventitial angiogenesis and lymphangiogenesis are stimulated by growth factors released by inflammatory cells in the vascular intima after balloon-induced endothelial injury.2. The severity of neointimal hyperplasia correlated with the number of adventitial microvessels, lymphatic vessels and the degree of infiltration of adventitial macrophages.3. Adventitial neogenetic blood vessels and lymphatic vessels promote intimal inflammation and hyperplasia probably via delivery and activation of inflammatory cells. BackgroundThe role of adventitia in providing cells and molecules with the capacity to influence neointimal formation and vascular remodeling has recently received considerable attention. Increasing experimental and human pathological evidence supports the concept that adventitia is not an innocent bystander but, rather, a positive participator in atherosclerosis and restenosis after angioplasty. Removal of the adventitia from large arteries results in intimal and medial hyperplasia characteristic of early atherosclerotic lesions. The mechanism of adventitial induction of neointimal proliferation could involve obstruction of the vasa vasorum, with subsequent vascular wall hypoxia. Neointimal formation was observed after the adventitia of rabbit carotid arteries was stripped, and interventions used to restore the adventitial vasa vasorum have been successful in inhibiting the development of intimal hyperplasia. But, the adventitial vasa vasorum of human coronary arteries could play a role in the formation of atherosclerotic plaque, and the density of newly formed vasa vasorum in response to injury could be proportional to vessel stenosis. This controversial evidence indicates another mechanism involved in intimal hyperplasia promoted by adventitia.Recent research has shown that inflammation plays a key role in coronary artery disease and other manifestations of atherosclerosis. The causal relation between adventitial inflammation and neointimal proliferation has been examined in pigs and rabbits. Adventitial inflammatory infiltration in close proximity to intimal atherosclerotic plaques has been known for a long time. A relation between the two processes seems obvious, since in normal (nonatherosclerotic) arteries, adventitial infiltration is notably absent, but once atherosclerosis has developed, adventitial inflammatory infiltration increases with the extent and severity of atherosclerotic plaque formation.Lymphatic vessels exist in adventitia in the atherosclerotic coronary artery. However, the functional consequences of lymphangiogenesis in adventitia are largely unknown. Since lymphatic vessels play an important role in the inflammatory and immune response, we hypothesized that adventitial lymphatic vessels may play an important role in neointimal formation and atherosclerosis.In the present study, we investigated the impact of angiogenesis and lymphangiogenesis on neointimal hyperplasia and detected changes in growth factors associated with angiogenesis and lymphangiogenesis in a rat model of removed carotid adventitia. In addition, we probed the time course, extent and molecular mechanism of lymphangiogenesis to clarify the role of adventitial lymphangiogenesis in neointimal hyperplasia. Aims1. To clarify the relation between neointimal hyperplasia and adventitial lymphangiogenesis and angiogenesis after removal of adventitia in the rat carotid artery.2. To probe the time course, extent and molecular mechanism of lymphangiogenesis-related growth factors VEGF-C, PDGF-B and their corresponding receptors VEGFR-3 and PDGFR-β.3. To investigate the correlation between lymphatic vessels and vascular inflammation and vascular-associated lymphoid tissue, intending to clarify the role of lymphatic vessel in atherosclerosis and vascular remodeling.Methods 1. Animal model Thirty male Wistar rats divided randomly into 3 groups, with 10 rats in each group. Rats were housed under constant room temperature (22℃) and a 12-h dark/12-h light cycle and fed a standard diet. All rats were anesthetized by intraperitoneal injection of pentobarbital (30 mg.kg-1); the left carotid artery was exposed and adventitia was removed by surgical knife carefully; the right carotid artery was taken as control material. Rats were sacrificed by .intraperitoneal injection of a lethal dose of phenobarbitone on day 7 (group 1), 14 (group 2), and 28 (group 3) after the procedure. Two-mm segments were cut from the proximal, middle and distal portions of the carotid artery and fixed with 4% phosphate-buffered formaldehyde for 24 h for immunohistochemical and morphometric analysis. The residual segments of the carotid were snap frozen in liquid nitrogen and stored at -80℃ for quantitative real-time RT-PCR analysis.2. Morphometric analysisCarotid segments were embedded in paraffin and cut into 6-um-thick sections, stained with hematoxylin and eosin and analyzed by use of Image-Pro Plus 5, paying particular attention to the intimal and medial thickness. The vascular area within the external elastic lamina (EELA) and the internal elastic lamina (IELA), as well as the lumen area (LA), were measured. The ratio of intimal to medial area (I/M) was calculated as I/M = (IELA- LA)/ (EELA - IELA). All parameters were measured from 3 sections selected from the proximal, middle and distal portion of the carotid segment, and values were averaged.3. AntibodiesThe primary goat polyclonal antibody against human CD34 (1:200) to identify blood endothelial cells, rabbit polyclonal antibody against human lymph vessel 1 (LYVE-1; 1:100) to tag lymphatic endothelial cells; rabbit polyclonal antibody against human CD68 (1:400) to mark macrophages, and rabbit polyclonal antibody against human vascular endothelial growth factor C (VEGF-C) (1:50) were from Santa Cruz Biotechnology (Santa Cruz, CA) and rabbit polyclonal antibody against platelet-derived growth factor B (PDGF-B). Secondary antibodies against rabbit and goat IgG were from Beijing Zhongshan Biotechnology Co. (ZSBIO, China).4. Immunohistochemistry Sections were deparaffinized and incubated with 5% goat serum or 5% BSA for 20 minutes and incubated with the primary antibodies overnight at 4℃ in a moisture chamber. The sections were then incubated with the appropriate secondary antibody for 30 min at room temperature. To inhibit any endogenous peroxidase activity, the sections were incubated with 0.3% H2O2 in absolute methanol for 30 min. A peroxidase substrate solution containing 0.02% H2O2 and 0.1% 3,3'-diaminobenzidine tetrahydrochloride (ZSBIO, China) in PBS was applied to display the reaction product in brown, and sections were then counterstained with hematoxylin. Incubation with PBS instead of the primary antibody was used as a negative control.5. Quantification of adventitial angiogenesis and lymphangiogenesisThe total number of micro vessels (CD34+) or lymph vessels (LYVE-1+) in the whole adventitia was counted under a light microscope. Vascular and lymph vessels were identified as morphologically circumferential brown products formed by one or more stained endothelial cells with at least one counterstained nucleus. In this case, a single brown dot was not counted. The number of adventitial microvessels (Ad-MV) and adventitial lymphatic vessels (Ad-LV) from 3 sections were counted by 2 independent investigators, and the mean values were derived.6. Real-time RT-PCRTotal RNA was extracted from the aortic tissue by use of Trizol (Invitrogen, Carlsbad, CA) following the manufacturer's protocol. RT-PCR was as described previously [15]. hi brief, 1 μg of RNA in 20 μl of volume was reverse transcribed with oligo (dT) primer by use of the M-MLV Reverse Transcriptase System (Promega, Madison, WI). The relative quantification of target genes was determined by use of the LightCycler (Roche Applied Science, USA) following the manufacturer's protocol. RT-PCR analysis involved use of a TaqMan probe. The reaction contained 0.2 μl of TaKaRa Ex Taq HS polymerase (TaKaRa Biotechnology, Dalian, China), 2 μl of 10 × buffer (Mg2+ plus), 2 μl dNTP mixture (1 mM, respectively), 1 μl of forward primer, 1 μl of reverse primer, 1 μl of probe and 1 μl of cDNA in a 20-μl final volume. The conditions for real-time PCR were as follows: denaturation at 95℃ for 30 s, and for 50 cycles, denaturation at 95℃, annealing for 10 s and extension at 72 ℃ for 10 s. Primer and probe sequences (Sangon, Shanghai, China) are in Table 1. Target geneexpression was calculated by use of the 2△△Ct method and expressed as fold differencebetween experimental groups and control group after normalizing to reference geneexpression7. Statistical analysisData analysis involved use of SPSS 11.5. All data are expressed as mean ± SD. One-way ANOVA was used to compare the differences among groups. The correlation among the number of adventitial lymph vessels, microvessels, macrophage index (proportion of macrophage number to total cell number and I/M ratio were tested by Pearson's correlation analysis. A P<0.05 was considered significant. Results1. Lymphangiogenesis after adventitia removalAs compared with control arteries, arteries lacking adventitia showed increased Ad-LV beginning on day 7 after adventitia removal (5.40±0.97 vs. 2.10±0.74, P<0.001) and peaking on day 14 (11.50±1.08 vs. 2.5G±0.53, P<0.001). The value of Ad-LV remained high on day 28 after adventitia removal as compared with that on day 14(10.90±0.99vs. 11.50±1.08, P>0.05).2. Angiogenesis after adventitia removalAs compared with control arteries, arteries lacking adventitia showed increased Ad-MV, similar to the pattern of Ad-LV change, beginning on day 7 after adventitia removal (11.90±0.99 vs.6.10±0.99, P<0.001). The value of Ad-MV increased even greater on day 14 (18.50±0.85 vs. 11.90±0.99, P<0.001) and day 28 (17.70±1.06 vs. 11.90±0.99, P<0.001) as compared with that on day 7.3. Relation among lymphangiogenesis, angiogenesis and neointimal hyperplasiaThe carotid intima appeared as a single cell layer, the IELA was intact and the EELA was in close contact with the adventitia in control arteries. Hyperplastic intima of multiple layers of vascular smooth muscle cells (VSMCs) became evident on day 7 after adventitia removal and peaked on day 14 (0.33±0.03 vs. 0.13±0.02, P<0.001) . However, the I/M ratio was not further increased on day 28 as compared with day 14 (0.31±0.01 vs.0.33±0.03, P>0.05). Ad-LV was significantly correlated with I/M ratio on days 7, 14 and 28 (r=0.745, P=0.013; i=0.781, P=0.008 and i=0.711, P=0.021, respectively), with the highest correlation on day 14 after adventitia removal. Ad-MV and I/M ratio were not correlated on any of the days, and Ad-LV, Ad-MV and I/M ratio were not correlated in the control group.4. Macrophage distribution in the carotid wallImmunohistochemical staining revealed CD68+ cells predominantly located in the adventitia. The macrophage index was increased on day 7 (10.00%±1.89% vs. 1.80%±0.79%, P<0.001), peaked on day 14 (12.40%±1.43% vs. 2.00%±0.67%, PO.001), and maintained at a high level on day 28 (11.50%%±1.65%% vs. 2.10%±0.74%, P<0.001) as compared with that in the control group. The macrophage index was significantly correlated with I/M ratio on especially day 14 and on day 28 (r=0.933, P=0.000; r=0.714, P=0.020, respectively).5. VEGF-C and PDGF-BB expression in the carotid wall Immunohistochemical staining revealed no VEGF-C and PDGF-B expression inthe control group. VEGF-C was expressed in macrophages on days 7 and 14 in the whole carotid wall and only in macrophages in adventitia on day 28. PDGF-B expression was mainly found in VSMCs and endothelial cells on days 7 and 14 but was undetectable on day 28 after adventitia removal.6. mRNA expression of VEGF-C , VEGFR-3, PDGF-B and PDGFR-βThe mRNA expression of VEGF-C, VEGFR-3, PDGF-B and PDGFR-β reached a plateau on day 7 after adventitia removal, with VEGF-C, VEGFR-3 and PDGF-BB showing significantly increased expression on day 14. Conclusion1. Angiogenesis and lymphangiogenesis appeared in adventitia after it was stripped.2. The number of lymphatic vessels and the extnt of macrophage infiltration correlated with neointimal hyperplasia.2. Neogenetic lymph vessels, in turn, promote intimal inflammation and hyperplasia,via delivery of inflammatory cells.
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