细胞色素P450基因降低动脉粥样硬化小鼠MMP-9表达

目的研究血管内皮高表达CYP2C8基因能否降低动脉粥样硬化小鼠的MMP-9的表达。方法以20周龄APOEKO+/-CYP2C8Tg+/-和CYP2C8Tg+/-小鼠(n=10/组)为研究对象,相同基因背景和周龄的同窝APOEKO+/-和C57BL/6小鼠设为对照。采用PCR技术鉴定小鼠CYP2C8+/-基因;油红O染色检测APOEKO+/-CYP2C8Tg+/-、CYP2C8Tg+/-、APOEKO+/-和C57BL/6小鼠主动脉斑块形成面积;用Real-time PCR法检测各组小鼠的主动脉MMP-9基因表达水平,Western blot分析各组小鼠的主动脉MMP-9蛋白的表达情况。用ELISA法检测各组小鼠的血浆IL-1β和IL-10。结果 APOEKO+/-CYP2C8Tg+/-和CYP2C8Tg+/-小鼠主动脉斑块形成面积明显减少,Real-time PCR分析显示高表达CYP2C8在主动脉中明显下调MMP-9基因的表达,Western blot分析结果显示:高表达CYP2C8在主动脉中明显下调MMP-9蛋白的活性。在血清学上,高表达CYP2C8明显上调IL-10而下调IL-1β。结论高表达CYP2C8基因能够降低小鼠的MMP-9的活性、减低炎性介质水平,通过抗炎和稳定粥样斑块而发挥抗粥样硬化作用。     

细胞色素P450基因对高脂饮食诱导不同周龄小鼠动脉粥样硬化的保护作用机制

目的在高脂饮食诱导小鼠动脉粥样硬化中研究CYP2C8基因对动脉粥样硬化的作用及相关机制。方法 :以20和40周龄APOEKO+/-CYP2C8Tg+/-和CYP2C8Tg+/-转基因的小鼠为研究对象,相同基因背景和周龄的同窝APOEKO+/-和C57BL/6小鼠设为对照。在第5,20,40周时测各组动物EET含量,用Real-time PCR法检测各组小鼠的主动脉PPAR-γ和MCP-1基因表达水平,Western blot分析各组小鼠的主动脉(p-)eNOS和NF-κB蛋白的表达与小鼠的肝脏PI3K、(p-)AKT、(p-)ERK和(p-)P38等信号通路蛋白的表达情况。结果 :在高脂饮食中,CYP2C8Tg+/-组和APOEKO+/-CYP2C8Tg+/-组的EET浓度明显增高。Western blot显示:高表达CYP2C8在肝脏中明显上调PI3K、(p-)AKT、(p-)ERK和(p-)P38蛋白;在主动脉明显上调(p-)eNOS蛋白,下调NF-κB蛋白。Real-time PCR分析显示高表达CYP2C8在主动脉中下调MCP-1蛋白。结论 :本研究高表达CYP2C8基因具有显著的抗炎作用,这一作用是...     

载脂蛋白E基因敲除小鼠动脉粥样硬化早期血管外膜血管细胞黏附分子1和细胞间黏附分子1的表达

目的探讨血管外膜血管细胞黏附分子1和细胞间黏附分子1在动脉粥样硬化病灶形成及发展中的作用。方法 6周龄载脂蛋白E基因敲除小鼠和野生型C57BL/6小鼠,高脂饮食喂养2、4和8周,选取升主动脉制备连续切片,部分切片行Movat染色,观察组织形态学变化并测量外膜厚度的变化;部分切片用免疫组织化学法观察不同阶段血管外膜及内膜血管细胞黏附分子1和细胞间黏附分子1表达的动态变化。结果 6周龄载脂蛋白E基因敲除小鼠和各个时间点的C57BL/6小鼠均未观察到内膜损伤的任何迹象,主动脉外膜厚度亦无显著变化,外膜均无血管细胞黏附分子1的表达;高脂喂养2周后,载脂蛋白E基因敲除小鼠血管外膜厚度增加,但在内膜仍无肉眼可见病灶,此时外膜血管细胞黏附分子1呈现弱阳性表达;高脂喂养4周和8周后,载脂蛋白E基因敲除小鼠血管外膜厚度逐渐增加,内膜出现泡沫细胞,纤维斑块,外膜及内膜损伤处血管细胞黏附分子1表达增强。载脂蛋白E基因敲除小鼠随着高脂喂养时间延长,主动脉外膜及内膜细胞间黏附分子1的表达也增加,但C57BL/6小鼠血管外膜细胞间黏附分子1表达量少且稳定,各时间点之间无明显差异。结论载脂蛋白E基因敲除小鼠随着高脂喂养时间延长血管外膜血管细胞黏附分子1和细胞间黏附分子1的表达增加。     

Orai1在载脂蛋白E基因敲除小鼠动脉粥样硬化斑块形成中的表达

目的探讨Orai1在载脂蛋白E基因敲除(Apo E-/-)小鼠动脉粥样硬化斑块形成过程中的表达。方法选取7~8周龄雄性Apo E-/-小鼠及野生型C57BL/6J小鼠,高脂饲喂20、27和33周后,在各个时点处死动物。取主动脉制备连续切片,HE、Masson染色计算机图像分析仪测定斑块面积占管腔面积百分比,及胶原成分占斑块面积百分比;油红O染色分析斑块中脂质含量;免疫组织化学染色测定平滑肌细胞阳性表达Orai1的百分比;Western Blot定量分析Orai1在易损斑块形成过程中的动态表达。结果与同周龄C57BL/6J小鼠相比,Apo E-/-小鼠主动脉Orai1表达增高,且随着其周龄增加,Orai1在Apo E-/-小鼠主动脉的表达动态升高(P0.05)。结论 Orai1参与动脉粥样硬化斑块形成的病理过程,在其形成过程中其表达上调。     

动脉粥样硬化斑块内FIZZ1表达促进平滑肌细胞清道夫受体-A上调

目的探讨ApoE基因敲除鼠动脉粥样硬化斑块内FIZZ1表达情况及其对平滑肌细胞清道夫受体A(SR-A)表达的影响.方法C57BL/6J ApoE基因敲除鼠及C57BL/6J野生型小鼠各9只,分别喂养高脂饲料及普通饲料,24周后处死小鼠,石蜡包埋血管后做连续切片,行HE染色及FIZZ1免疫组化.用氧化型低密度脂蛋白(ox-LDL)以及终浓度分别为3×10-6mmol/L、9×10-6mmol/L、2.7×10-5mmol/L的FIZZ1刺激培养的平滑肌细胞,激光共聚焦显微镜确认SR-A表达后,流式细胞术检测FIZZ1对ox-LDL诱导的平滑肌细胞SR-A表达的影响.结果ApoE基因敲除鼠高脂饲养24周后,主动脉根部明显形成动脉粥样硬化,可见FIZZ1在动脉粥样硬化斑块内明显表达,同龄野生型C57BL/6J鼠正常血管壁内,未见FIZZ1表达,重组FIZZ1能明显促进ox-LDL诱导的平滑肌细胞SR-A表达(与对照组比较,P<0.01).结论C57BL/6J野生型小鼠正常血管不表达FIZZ1,C57BL/6JApoE基因敲除鼠动脉粥样斑块表达FIZZ1,FIZZ1促进ox-LDL诱导的平滑肌细胞SR-A表达,提示FIZZ1可能在ApoE基因敲除鼠动脉粥样硬化进展中起一定的促进作用.     

载脂蛋白E基因敲除小鼠动脉粥样硬化早期血管外膜成纤维细胞表型转化为肌成纤维细胞

目的　探讨动脉外膜成纤维细胞表型转化与早期动脉粥样硬化病灶形成的关系。　方法　选择6周龄载脂蛋白E基因敲除小鼠和野生型C57BL/6小鼠,高脂喂养2、4和8周后,在各个时间点处死动物后选取升主动脉制备连续切片,用免疫组织化学方法观察不同时间血管外膜α平滑肌肌动蛋白及转化生长因子β₁的表达变化。体外培养高脂喂养2周的载脂蛋白E基因敲除小鼠和C57BL/6小鼠动脉外膜成纤维细胞,免疫荧光染色检测α平滑肌肌动蛋白的表达,通过透射电镜观察细胞超微结构,Western　Blot检测α平滑肌肌动蛋白及转化生长因子β₁蛋白的表达。结果　体内实验发现载脂蛋白E基因敲除小鼠高脂喂养2周、4周后血管外膜检测到α平滑肌肌动蛋白的阳性表达,8周后呈现弱阳性,随高脂喂养时间增加,载脂蛋白E基因敲除小鼠主动脉外膜细胞转化生长因子β₁表达增强。而C57BL/6小鼠血管外膜细胞一直未检测到α平滑肌肌动蛋白及转化生长因子β₁的阳性表达。体外实验观察到载脂蛋白E基因敲除小鼠血管外膜成纤维细胞部分表现为α平滑肌肌动蛋白阳性,肌丝明显增多,　α平滑肌肌动蛋白及转化生长因子β₁蛋白表达水平都明显高于野生型C57BL/6小鼠（P<0.05）,而C57BL/6小鼠血管外膜成纤维细胞则表现为α平滑肌肌动蛋白阴性,超微结构无明显改变。结论　动脉粥样硬化病灶形成早期血管外膜成纤维细胞表型即转化为肌成纤维细胞。     

瑞舒伐他汀对载脂蛋白E基因敲除小鼠血管内皮黏附性的影响

目的 观察瑞舒伐他汀抗血管壁炎症的作用.方法 载脂蛋白E基因敲除小鼠80只和C57BL/6小鼠20只,均为8～9周龄.分为2周药物处理组和6周药物处理组,每组各40只载脂蛋白E基因敲除小鼠和10只C57BL/6小鼠.载脂蛋白E基因敲除小鼠每日1次皮下注射不同浓度的瑞舒伐他汀,剂量分别为0、1、5和20 mg/kg.药物处理满2周或6周时,心内穿刺取血,并收获小鼠主动脉.结果 经瑞舒伐他汀处理2周或6周后,载脂蛋白E基因敲除小鼠血浆总胆固醇和低密度脂蛋白胆固醇明显下降,但甘油三酯和高密度脂蛋白胆固醇均无明显变化.经瑞舒伐他汀处理2周后,20 mg/kg组载脂蛋白E基因敲除小鼠主动脉内皮一单核细胞黏附率有明显下降;经瑞舒伐他汀处理6周后,5、20 mg/kg组载脂蛋白E基因敲除小鼠主动脉内皮一单核细胞黏附率均有明显下降.经定量RT-PCR分析,瑞舒伐他汀20 mg/kg能明显抑制载脂蛋白E基因敲除小鼠主动脉VCAM-1、MCP-1 mRNA表达.结论 瑞舒伐他汀具有抑制动脉粥样硬化早期炎症反应的作用.     

FIZZ1在ApoE基因敲除鼠动脉粥样斑块中的表达

背景FIZZ1是一种与炎症相关的缺氧诱导的有丝分裂因子,在肺部疾病缺氧状态下具有刺激肺动脉平滑肌细胞增殖等作用。目的探讨FIZZ1在ApoE基因敲除鼠粥样斑块表达情况及其对平滑肌细胞增殖的影响。方法应用C57BL/6J ApoE基因敲除鼠构建动脉血管粥样硬化模型并与普通C57BL/6J野生型小鼠进行对照研究,通过对动脉血管HE染色及FIZZ1免疫检测斑块FIZZ1表达,同时给以不同浓度FIZZ1刺激培养的平滑肌细胞,MTT法测定FIZZ1对平滑肌细胞增殖的影响。结果ApoE基因敲除鼠高脂饲养24周后,主动脉根部明显形成动脉粥样硬化,斑块体积较大,免疫组化可见FIZZ1在粥样硬化斑块内明显表达,同龄野生型C57BL/6J鼠血管壁内,未见FIZZ1表达,重组FIZZ1能促进体外培养的平滑肌细胞增殖(与对照组比较,差别具有统计学意义,P<0.05)。结论C57BL/6J野生型小鼠正常血管不表达FIZZ1,C57BL/6J ApoE基因敲除鼠粥样斑块表达FIZZ1,FIZZ1具有促进平滑肌细胞增殖的作用,提示其可能在动脉粥样硬化进展中起一定的作用。     

FIZZ1在ApoE基因敲除鼠动脉粥样斑块中的表达

背景 FIZZ1是一种与炎症相关的缺氧诱导的有丝分裂因子,在肺部疾病缺氧状态下具有刺激肺动脉平滑肌细胞增殖等作用. 目的 探讨FIZZ1在ApoE基因敲除鼠粥样斑块表达情况及其对平滑肌细胞增殖的影响.方法 应用C57BL/6J ApoE基因敲除鼠构建动脉血管粥样硬化模型并与普通C57BL/6J野生型小鼠进行对照研究,通过对动脉血管HE染色及FIZZ1免疫检测斑块FIZZ1表达,同时给以不同浓度 FIZZ1刺激培养的平滑肌细胞,MTT法测定FIZZ1对平滑肌细胞增殖的影响.结果 ApoE基因敲除鼠高脂饲养24周后,主动脉根部明显形成动脉粥样硬化,斑块体积较大,免疫组化可见FIZZ1在粥样硬化斑块内明显表达,同龄野生型C57BL/6J鼠血管壁内,未见FIZZ1表达,重组FIZZ1能促进体外培养的平滑肌细胞增殖(与对照组比较,差别具有统计学意义,P＜0.05).结论 C57BL/6J野生型小鼠正常血管不表达FIZZ1,C57BL/6J ApoE基因敲除鼠粥样斑块表达FIZZ1,FIZZ1具有促进平滑肌细胞增殖的作用,提示其可能在动脉粥样硬化进展中起一定的作用.     

肺炎衣原体感染对C57BL/6J小鼠动脉粥样硬化形成的影响

目的:研究肺炎衣原体(CP)感染对C57BL/6J小鼠动脉粥样硬化(AS)形成的影响。方法:48只8周龄雄性C57BL/6J小鼠分为感染-高脂组、高脂组和感染组和对照组,喂养40周,取主动脉根部标本分析AS斑块面积,采用直接免疫荧光法检查血管壁CP抗原,微量免疫荧光法(Micro-IFA)检测CP特异性抗体IgG。结果:感染-高脂组小鼠平均AS斑块面积较高脂组增大[(135249±43748)μm2∶(96378±30945)μm2,P<0·05],感染组和对照组小鼠无AS样斑块形成。结论:CP感染可加速高脂饮食C57BL/6J小鼠的主动脉AS发展。     

Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse

AIM： To ascertain whether constitutive androstane receptor （CAR） activation by 1,4-bis-[2-（3,5,- dichloropyridyloxy）] benzene （TCPOBOP） modulates steatohepatitis in the methionine choline-deficient （MCD） diet-fed animal.METHODS： C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol.RESULTS： Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis （44.6 ＋ 5.4% vs 30.4 ＋ 4.5%, P 〈 0.05） and serum triglyceride levels （48 ＋ 8 vs 20 ＋ 1 mg/dL, P 〈 0.05） in MCD diet- fed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal co-oxidation and peroxisomal p-oxidation, namely CYP4A10, LPBE, and 3-ketoacyI-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters.CONCLUSION： CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.     

Decreased arteriolar density in endothelial nitric oxide synthase knockout mice is due to hypertension, not to the constitutive defect in endothelial nitric oxide synthase enzyme

BACKGROUND : Hypertension in endothelial nitric oxide synthase knockout (eNOS-/-) mice is believed to be partly due to altered vasodilatation. However, nitric oxide (NO) is also known to play an important part in angiogenesis. OBJECTIVE : To investigate whether capillary and arteriolar density were impaired in eNOS-/- mice, as this could account for increased vascular resistance and hypertension. METHODS : Using immunohistochemistry with mouse monoclonal smooth muscle alpha-actin antibody to detect arterioles and rabbit polyclonal fibronectin antibody to detect capillaries, we quantified arteriolar and capillary density in the left ventricle and in the gracilis muscle from eNOS-/- mice compared with those in C57BL6J littermates (n = 6-8) in 8- and in 12-week-old mice. In a second set of experiments, we treated 8-week-old normotensive eNOS-/- mice with the antihypertensive vasodilator, hydralazine, for 1 month. RESULTS : Eight-week-old eNOS-/- mice were normotensive and presented similar arteriolar and capillary densities in cardiac and skeletal muscles compared with those in eNOS+/+ mice. Twelve-week-old eNOS/- mice were hypertensive (mean arterial pressure 118 +/- 21 mmHg compared with 64 +/- 2 mmHg; P < 0.05). Capillary densities were similar in eNOS-/- mice and eNOS+/+ mice in the heart (4154 +/- 123 and 4051 +/- 247/mm2, respectively) and in skeletal muscle (961 +/- 40 and 1025 +/- 41/mm2, respectively). Arteriolar densities were 15% lower in skeletal muscle and in the heart in eNOS-/- mice than in the eNOS+/+ control group (P < 0.05). Hydralazine prevented hypertension and arteriolar rarefaction in eNOS-/- mice, whereas capillary density was unaffected by treatment with the vasodilator. CONCLUSION : In young non-hypertensive eNOS-/- mice, the lack of eNOS did not affect microvascular densities in either of the muscles studied. In adult hypertensive eNOS-/- mice, we observed a lower arteriolar density, but a similar capillary density compared with controls. Hydralazine prevented hypertension and arteriolar rarefaction in adult mice, suggesting a non-NO-dependent pathway. Capillary density was not affected by hydralazine.     

Induction of inducible nitric oxide synthase,argininosuccinate synthase,and GTP cyclohydrolase I in arthritic joints of human tumor necrosis factor-alpha transgenic mice

OBJECTIVE: Transgenic mice that express human tumor necrosis factor-alpha (Tg197 h-TNF-alpha) develop polyarthritis at 3 to 4 weeks of age leading to severe joint destruction at 8 to 10 weeks of age. Studies have suggested that inducible nitric oxide synthase (iNOS) activity can modulate the progression of arthritis. We investigated the induction of iNOS together with argininosuccinate synthase (AS) and GTP cyclohydrolase I (GTPCH), 2 of the rate-limiting enzymes for high output NO generation, in the Tg197 h-TNF-alpha transgenic model of arthritis. METHODS: We used 4 and 8-week-old Tg197 h-TNF-alpha transgenic mice and wild-type CBA C57B1/6 control mice to investigate the expression of iNOS with respect to that of AS, GTPCH, and 3-nitrotyrosine by quantitative RT-PCR and immunocytochemistry. Urinary NO metabolites were analyzed using a chemiluminescence assay. RESULTS: Inducible NOS, AS, and GTPCH mRNA was found in all study groups; however, only iNOS mRNA showed a clear increase in 4-week-old Tg197 h-TNF-alpha transgenics in comparison to age matched wild-type controls. Abundant iNOS protein expression was found in macrophages and vascular smooth muscle cells in hyperplastic synovium and pannus. AS expression was found in vascular endothelium and fibroblasts of the inflammatory synovium and pannus. GTPCH immunoreactivity was mostly restricted to macrophages in inflammatory synovium. Localization of 3-nitrotyrosine overlapped with that of iNOS, indicating formation of reactive nitrogen species. Consistent with the high output NO generation, there was a 5-fold increase in urinary NO metabolites in 8-week-old Tg197 h-TNF-alpha transgenic mice. CONCLUSION: We characterized the Tg197 h-TNF-alpha transgenic model of inflammatory arthritis in terms of high output NO-generating pathway, and showed that both AS and GTPCH are intimately associated with inflammatory arthritis. The concomitant induction of AS and GTPCH with that of iNOS suggests that they may be important modulators of arthritis, and that they may represent novel targets for modulation of disease activity.     

Effect of macrophage-derived apolipoprotein E on established atherosclerosis in apolipoprotein E-deficient mice

Apolipoprotein E-deficient (apoE(-/-)) mice have hyperlipidemia and develop spontaneous atherosclerosis in a time-dependent manner. Although macrophage-derived apoE has been shown to prevent the development of atherosclerosis in apoE(-/-) mice, whether it would induce regression of established atherosclerosis is unknown. To determine this, 8-week-old apoE(-/-) mice were transplanted with apoE(+/+) bone marrow. Four weeks after transplantation, when plasma cholesterol levels had reached normal levels, a group of mice (n=12) were killed and their aortic lesions were measured and used as a baseline to judge regression. Twelve and 20 weeks after transplantation, aortic lesion areas of the mice were 9340+/-2184 micrometer(2) (mean+/-SEM, n=8) and 12 211+/-1433 micrometer(2) (n=9), respectively, values not significantly different from the lesion areas of the baseline mice (12 347+/-2487 micrometer(2); n=12, P>0.05). In contrast, apoE(-/-) mice reconstituted with apoE(-/-) bone marrow developed severe atherosclerotic lesions (453 036+/-29 767 micrometer(2), n=7) 20 weeks after transplantation. These data suggest that macrophage-derived apoE was insufficient to induce significant regression of established atherosclerotic lesions in apoE(-/-) mice, although it was sufficient to eliminate hypercholesterolemia and prevent progression of aortic lesions.     

Evidence for differential expression of candida albicans virulence genes during oral infection in intact and human immunodeficiency virus type 1-transgenic mice

To comprehensively assess the in vivo expression of Candida albicans hydrolytic enzyme genes during oropharyngeal candidiasis (OPC), a controlled sequential analysis of the temporal expression of individual members of the SAP (secretory aspartyl proteinase) gene family and PLB1 (phospholipase B) in a murine model of OPC was conducted. Acute infections in intact C3H and DBA/2 mice were terminated by clearance of C. albicans within 7 days after oral inoculation, but transgenic (Tg) mice expressing human immunodeficiency virus type 1 were persistently colonized until a final outgrowth before death. In contrast to the sustained expression of other SAP genes and PLB1, SAP7 and SAP8 were conspicuously distinguished by their transient expression in both intact and Tg mice. SAP5 and SAP9 were most strongly expressed throughout the course of infection in the Tg mice. These findings indicate that expression of individual members of the C. albicans SAP gene family is differentially regulated during experimental OPC.     

LONG-TERM EFFECT OF IODIZED OIL ON SERUM THYROGLOBULIN LEVELS IN ENDEMIC GOITRE PATIENTS

Serum thyroglobulin (Tg) response to bovine TSH (bTSH) was evaluated in 44 goitrous patients (grades III and IV) living in conditions of chronic iodine (I) deficiency (iodine urinary excretion less than 40 micrograms I/g) and in 26 normal subjects. After the initial clinical evaluation and laboratory tests (bTSH test, T4, T3, anti-Tg and anti-microsomal antibodies) all goitrous patients received 1 ml i.m. of iodized oil (I-oil) and were followed up for 30 months. The bTSH test was repeated at 6, 12, 20 and 30 months after I-oil in 21 subjects. A marked reduction in goitre size was observed in 85% of the patients with a concomitant significant increase in the mean serum T4 and T3 concentrations, a significant fall in the mean serum TSH level and a significant decrease in the T3/T4 ratio. Goitrous patients had elevated serum basal Tg levels (55 +/- 8 SEM micrograms/l) and a significantly mean higher peak Tg value after bTSH (200 +/- 65 micrograms/l) as compared with normal subjects (respectively, 11 +/- 1.4 and 32 +/- 3.4 micrograms/l). Larger goitres (grade IV) had a significantly higher mean peak Tg response as compared with grade III goitres. Treatment with I-oil significantly reduced the mean peak Tg response to bTSH after 6 months (59 +/- 10 micrograms/l) but at 12 and 20 months the peak Tg response after the injection rose, respectively, to 110 +/- 19 micrograms/l and 92 +/- 14 micrograms/l (P less than 0.02 as compared with 6 months), returning to the normal range only at 30 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative lymphatic, ocular, and metabolic phenotypes of Foxc2 haploinsufficient and aP2-FOXC2 transgenic mice

FOXC2 mutations cause the lymphatic/ocular disorder Lymphedema-Distichiasis (LD), and Foxc2 haploinsufficient mice mimic this disorder. To determine if FOXC2 overexpression might also cause lymphatic and/or ocular abnormalities, we performed dynamic lymphatic imaging (Evans blue dye), ocular tissue examination, and metabolic profiles in mice: transgenic for FOXC2 with an adipocyte (aP2) promoter (aP2-FOXC2 Tg), heterozygous for targeted disruption of Foxc2 (Foxc2+/-), or compound heterozygous and transgenic (Foxc2+/-, Tg) compared to wild-type controls (WT). Foxc2+/-; aP2-FOXC2 Tg; and Foxc2+/-, Tg, exhibited LD's distinctive hyperplastic lymphatic phenotype characterized by increased number of lymphatic channels and lymph nodes as well as retrograde lymph reflux. Foxc2+/-, and Foxc2+/-, Tg but not aP2-FOXC2 Tg or WT showed an abnormal ocular phenotype. Previously described alterations in brown/ white fat distribution and lean phenotype in aP2-FOXC2 transgenics were confirmed. AP2-FOXC2 Tg immunohistochemistry disclosed aberrant FOXC2 expression in ectopic sites, especially embryonic heart. Lymphatic system links with fat metabolism are discussed.