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Recent studies on human embryonic and fetal lungs show that the pulmonary arteries form by vasculogenesis. Little is known of the early development of the pulmonary veins. Using immunohistochemical techniques and serial reconstruction, we studied 18 fetal and neonatal lungs. Sections were stained with antibodies specific for endothelium (CD31, von Willebrand factor) and smooth muscle (alpha and gamma smooth muscle actin, smooth muscle myosin, calponin, caldesmon, and desmin) and antibodies specific for the matrix glycoprotein tenascin, the receptor protein tyrosine kinase EphB4, and its ligand ephrinB2. Kiel University-raised antibody number 67 (Ki67) expression allowed qualitative assessment of cell replication. By 34 d gestation, there was continuity between the aortic sac, pulmonary arteries, capillaries, pulmonary veins, and atrium. The pulmonary veins formed by vasculogenesis in the mesenchyme surrounding the terminal buds during the pseudoglandular period and probably by angiogenesis in the canalicular and alveolar stages. EphB4 and ephrinB2 did not distinguish between presumptive venous and arterial endothelium as they do in mouse. All venous smooth muscle cells derived directly from the mesenchyme, gradually acquiring smooth muscle specific proteins from 56 d gestation. Thus, both pulmonary arteries and veins arise by vasculogenesis, but the origins of their smooth muscle cells and their cytoskeletal protein content are different.
Am J Respir Cell Mol Biol 2002 Mar
PMID:Origin, differentiation, and maturation of human pulmonary veins. 1186 41

Cell differentiation markers on placental villi from the first trimester of human pregnancy have been studied by indirect immunofluorescence. Fluorescence labelling with antibodies against CD34 and CD31 was conspicuous in the vascular cells. The vascular paracellular clefts were labelled by anti-cadherin-5. A few vascular cells exhibited a positive reaction for von Willebrand factor, high-molecular-weight melanoma-associated-antibody and alpha-sm-actin compared to term pregnancy, indicating changes in protein expression during vascular differentiation. The poor anti-collagen IV reaction and the absence of a sm-myosin fluorescent signal observed around the vessels confirned the immaturity of the vessels. In contrast, strong reactions have previously been obtained with the latter antibodies in similar locations using term placental villi. A labelling was observed for antibodies against alpha3 and alpha5 integrins in these immature placental vessels suggesting cell-matrix interactions with specific domains of laminin or fibronectin. The vascular cells were also stained by anti-CD26. Surprisingly, the fetal vascular cells exhibited immunostainings in common with the villous cytotrophoblast (CD26) or the syncytiotrophoblast (cadherin-5) and cell islands cytotrophoblast (CD31, cadherin-5, alpha3 and alpha5 integrin subunits). These observations suggested a two step process for fetal vasculogenesis in the villi: i/ the formation of peripheral vessels induced by growth factors or cytokines derived from the nearby trophoblast, ii/ the development of muscular vessels due to growth factors or cytokines production induced by circulatory changes.
Cell Mol Biol (Noisy-le-grand) 2001
PMID:Characterization of first trimester human fetal placental vessels using immunocytochemical markers. 1193 78

A modern experimental strategy for treating myocardial ischemia is to induce neovascularization of the heart by the use of "angiogens", mediators that induce the formation of blood vessels, or angiogenesis. Studies demonstrated that coronary collateral vessels protect ischemic myocardium after coronary obstruction; therefore we sought to examine a novel method of stimulating myocardial angiogenesis through hypoxic preconditioning at both capillary (using anti-CD31) and arteriolar (using anti- alpha smooth muscle actin) levels and also investigate whether such treatments could preserve left ventricular contractile functional reserve and regional blood flow by increasing vascular endothelial growth factor (VEGF). Male Sprague-Dawley rats were randomly divided into four groups: normoxia+sham surgery (CS), normoxia+permanent left anterior descending coronary artery (LAD) occlusion (CMI), hypoxic preconditioning+sham surgery (HS) and hypoxic preconditioning+permanent LAD occlusion (HMI). Rats in the preconditioned groups were subjected to systemic hypoxemic hypoxic exposure (10+/-0.4% O(2)) for 4 h followed by a 24 h period of normoxic reoxygenation prior to undergoing LAD occlusion. Rats in the normoxia group were time matched with the preconditioned group and maintained under normoxic conditions for a 28 h period prior to LAD occlusion. Western blot analysis was performed to measure VEGF expression and TUNEL staining with endothelial cell-specific antibody, anti-VWF, was used to examine endothelial apoptosis. One, two and three weeks after the LAD occlusion, baseline left ventricular pressures were monitored and recorded. Pharmacological stress tests with dobutamine infusion in progressively increasing doses revealed significantly elevated contractile reserve at each dose point in the HMI group compared to the CMI group. The HMI group displayed statistically significant increases in capillary as well as arteriolar density after 1, 2 and 3 weeks post-operation. Blood flow was also significantly elevated in the HMI groups when compared to the CMI group. The extent of endothelial cell apoptosis was found to be inversely proportional to VEGF expression. It was concluded that hypoxic preconditioning stimulates myocardial angiogenesis to an extent sufficient to exert significant cardioprotection in a rat model of myocardial infarction progressing to heart failure as evidenced by increased capillary/arteriolar density and enhanced ventricular contractile functional reserve.
J Mol Cell Cardiol 2002 Mar
PMID:Hypoxic preconditioning triggers myocardial angiogenesis: a novel approach to enhance contractile functional reserve in rat with myocardial infarction. 1194 25

Tissue repair is driven by migratory macrophages and fibroblasts that infiltrate injury sites and secrete growth factors. We now report the enhancement of skeletal muscle repair by targeting transgene delivery to these repair cells using matrix-immobilized gene vectors. Plasmid and adenovirus vectors immobilized in collagen-gelatin admixtures were delivered to excisional muscle wounds, and when encoding either fibroblast growth factor-2 (FGF2) or FGF6 transgenes, produced early angiogenic responses that subsequently remodeled into arteriogenesis. FGF2 gene delivery enhanced the number of CD31(+) endothelial cells present at treatment sites > 6-fold by day 14, and muscular arteriole density up to 11-fold by day 21 (P<0.0001). Muscle repair was also enhanced, as FGF gene-treated wounds filled with regenerating myotubes expressing the marker CD56 (an average 20-fold increase in CD56 expression versus controls, P<0.0001). These responses required transfection of a threshold level of repair cells, achievable only in injured muscles, and were transgene-driven, as neither platelet-derived growth factor-B (PDGFB) gene nor FGF2 protein delivery produced equivalent responses. In conclusion, using biomatrices to direct gene delivery to repair cells allows for relatively complex regenerative processes such as arteriogenesis and myogenesis, and therefore represents a promising approach to treating injured and ischemic muscle.
Mol Ther 2002 May
PMID:Delivery of FGF genes to wound repair cells enhances arteriogenesis and myogenesis in skeletal muscle. 1199 42

Collagen degradation is required for the creation of new integrin binding sites necessary for cell survival. However, a complete separation between the matrix and the cell leads to apoptosis, dilatation, and failure. Previous studies have demonstrated increased metalloproteinase activity in the failing myocardium. To test the hypothesis that disintegrin metalloproteinase (DMP) is induced in human heart end-stage failure, left ventricle tissue from ischemic cardiomyopathic (ICM, n = 10) and dilated cardiomyopathic (DCM, n = 10) human hearts were obtained at the time of orthotopic cardiac transplant. Normal (n = 5) tissue specimens were obtained from unused hearts. The levels of reduced oxygen species (ROS) were 12 +/- 2, 25 +/- 3, and 16 +/- 2 nmol (means +/- SE, P < 0.005) in normal, ICM, and DCM, respectively, by spectrofluorometry. The percent levels of endothelial cells were 100 +/- 15, 35 +/- 19, and 55 +/- 11 in normal, ICM, and DCM, respectively, by CD31 labeling. The levels of nitrotyrosine by Western analysis were significantly increased, and endothelial nitric oxide (NO) by the Griess method was decreased in ICM and DCM compared with normal tissue. The synthesis and degradation of beta(1)-integrin and connexin 43 were significantly increased in ICM and DCM compared with normal hearts by Western analysis. Levels of DMP were increased, and levels of cardiac inhibitor of metalloproteinase (CIMP) were decreased. Aggrecanase activity of DMP was significantly increased in ICM and DCM hearts compared with normal. These results suggest that the occurrence of cardiomyopathy is significantly confounded by the increase in ROS, nitrotyrosine, and DMP activity. This increase is associated with decreased NO, endothelial cell density, and CIMP. In vitro, treatment of CIMP abrogated the DMP activity. The treatment with CIMP may prevent degradation of integrin and connexin and ameliorate heart failure.
Am J Physiol Lung Cell Mol Physiol 2002 Aug
PMID:Induction of oxidative stress and disintegrin metalloproteinase in human heart end-stage failure. 1211 83

Staphylococcal scalded skin syndrome (SSSS) results from the effect of exfoliative-toxins produced by staphylococcal strains. The disease affects predominantly children, and is rare in adults. We report two cases of the adult type of SSSS. Corticotherapy, chronic alcohol abuse and epilepsy-related immune changes might have been predisposing factors in these patients. The immunopathological characteristics of the inflammatory cell infiltrate in adults SSSS have not been thoroughly explored so far in the literature. Biopsies from 2 patients with bullous SSSS skin were studied by means of immunochemistry using a panel of 10 antibodies directed to FXIIIa, CD15, CD31, CD45R0, CD50, CD54, CD62E, CD95, CD106, and L1-protein, respectively. Cutaneous biopsies from related blistering diseases were compared. They included drug-induced toxic epidermal necrolysis (TEN), bullous impetigo and superficial pemphigus. A dense cell infiltrate composed of granulocytes (CD15+), macrophages (L1 protein+) and memory T cells (CD45R0+) and a strong expression of ICAM-3 (CD50) were present in the epidermis. CD95+ keratinocytes were lining the intraepidermal blisters. Type I dermal dendrocytes (Factor XIIIa+) were numerous and plump in the dermis. Bullous impetigo exhibited the same pattern of inflammatory cells, but with a lower density in type I dermal dendrocytes. TEN differed from SSSS by both the absence of CD15+ granulocytes and a stronger expression of the pro-apoptotic CD95 antigen in the epidermis. In superficial pemphigus, CD95 antigen was not expressed, and CD15+ granulocytes, CD45R0+ lymphocytes and L1 protein+ monocytes were much less numerous. It is concluded that the specific binding of SSSS-induced exotoxins to the desmosomes alters the keratinocyte metabolism leading to an inflammatory reaction followed by focal apoptosis. Our findings are in line with the concept that SSSS exotoxins might be superantigens. A common pathomechanism leading to epidermal destruction is likely operative in SSSS and bullous impetigo. The inflammatory cell composition in TEN and superficial pemphigus markedly differs from that in SSSS.
Int J Mol Med 2002 Dec
PMID:Differential pathomechanisms of epidermal necrolytic blistering diseases. 1242 94

Vascularization defects in genetic recombinant mice have defined critical roles for a number of specific receptor tyrosine kinases. Here we evaluated whether an endothelium-expressed receptor tyrosine phosphatase, CD148 (DEP-1/PTPeta), participates in developmental vascularization. A mutant allele, CD148(DeltaCyGFP), was constructed to eliminate CD148 phosphatase activity by in-frame replacement of cytoplasmic sequences with enhanced green fluorescent protein sequences. Homozygous mutant mice died at midgestation, before embryonic day 11.5 (E11.5), with vascularization failure marked by growth retardation and disorganized vascular structures. Structural abnormalities were observed as early as E8.25 in the yolk sac, prior to the appearance of intraembryonic defects. Homozygous mutant mice displayed enlarged vessels comprised of endothelial cells expressing markers of early differentiation, including VEGFR2 (Flk1), Tal1/SCL, CD31, ephrin-B2, and Tie2, with notable lack of endoglin expression. Increased endothelial cell numbers and mitotic activity indices were demonstrated. At E9.5, homozygous mutant embryos showed homogeneously enlarged primitive vessels defective in vascular remodeling and branching, with impaired pericyte investment adjacent to endothelial structures, in similarity to endoglin-deficient embryos. Developing cardiac tissues showed expanded endocardial projections accompanied by defective endocardial cushion formation. These findings implicate a member of the receptor tyrosine phosphatase family, CD148, in developmental vascular organization and provide evidence that it regulates endothelial proliferation and endothelium-pericyte interactions.
Mol Cell Biol 2003 Mar
PMID:A mutant receptor tyrosine phosphatase, CD148, causes defects in vascular development. 1258 99

Smooth muscle cells (SMC) and endothelial cells (EC) play a pivotal role in arteriogenesis and atherosclerosis. We evaluated the role of EC on the growth of SMC and neonatal cardiomyocytes (NEO) by using serum-free EC-supernatant (AoCM). Five percent fetal calf serum was used in order to mimic growth effects of blood. EC and SMC purities were 99% as determined by absence or presence of markers such as CD31, desmin, alpha-smooth muscle actin and tropomyosin using immunostaining and FACS analysis. AoCM markedly influenced the morphology of NEO as determined by alpha-actinin staining but showed only little effect on the phenotype of SMC. Protein synthesis after 2 days increased 2.5-fold in SMC and 3.7-fold in NEO as determined by tritium incorporation. The values for serum (2.8 and 2.3-fold, respectively) were comparable. The induction of DNA-synthesis by serum in NEO was twice that of AoCM (3.9-fold). However, proliferative effects of serum and AoCM on SMC differed markedly: Serum induced a 66-fold increase in DNA-synthesis resulting in a 54% higher cell number. DNA-synthesis after AoCM treatment lead to a nonsignificant small increase and no proliferation was detected. Platelet derived growth factor (PDGF-AB), present in blood, induced a 47-fold increase in DNA-synthesis and a 38% increase in cell number. Our data suggest that EC in the absence of physical forces exert strong morphogenic effects on cardiomyocytes but they lack specific effects on smooth muscle cells. In vessels EC might function as a border to isolate SMC from key regulators in blood such as PDGFs.
Mol Cell Biochem 2003 Jan
PMID:Porcine aortic endothelial cells show little effects on smooth muscle cells but are potent stimulators of cardiomyocyte growth. 1261 64

The vascular endothelial growth factor (VEGF) and its interaction with the vascular endothelial growth factor receptor 2 [VEGFR2/murine fetal liver kinase 1 (Flk-1), human kinase domain receptor] are an important angiogenic pathway leading to tumor vascularization. A plasmid DNA encoding the complete extracellular domain (ECD) of murine Flk-1 including the endogenous signal sequence was designed as a possible competitor of the receptor to sequester VEGF. The plasmid DNA was used to treat B16F10 cell-induced subcutaneous melanomas in syngeneic mice. The Flk-1 ECD-encoding plasmid DNA injected intramuscularly did not lead to tumor reduction. However, intratumoral injection caused a dose-dependent reduction and significant retardation of tumor growth. Blood vessels analyzed by immunohistochemistry with anti-CD31 antibodies as indicators of vascularization appeared smaller in diameter after treatment. A combination of Flk-1 ECD and DNA encoding murine interleukin-12 or murine interferon-gamma inducible protein-10 improved the effect, leading to tumor regression and long-term survival of the mice.
J Mol Med (Berl) 2003 Apr
PMID:A combination of plasmid DNAs encoding murine fetal liver kinase 1 extracellular domain, murine interleukin-12, and murine interferon-gamma inducible protein-10 leads to tumor regression and survival in melanoma-bearing mice. 1268 54

Exposure to hypoxia leads to the development of pulmonary hypertension (PH) as a consequence of pulmonary smooth muscle hyperplasia. Hypoxia concomitantly stimulates lung expression of angiogenic factors. To investigate the role of angiogenesis processes in development of hypoxic PH, we examined the effects of lung overexpression of angiostatin, an angiogenesis inhibitor, on development of hypoxic PH and lung endothelial cell (EC) density. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molcule driven by the cytomegalovirus promoter (Ad.K3). Comparison was made with a control vector containing no gene in the expression cassette (Ad.CO1). Treatment with Ad.K3 (300 plaque-forming units [pfu]/cell) inhibited cultured human pulmonary artery EC migration by 100% and proliferation by 50%, but was without effects on human pulmonary artery smooth muscle cells. After intratracheal administration of Ad.K3 (109 pfu) to mice, angiostatin protein became detectable in bronchoalveolar lavage fluid. Mice pretreated with Ad.K3 1 d before a 2-wk exposure to hypoxia (10% O2) showed more severe pulmonary hypertension than Ad.CO1-pretreated controls, as assessed by higher right ventricular systolic pressure (36.5 +/- 2.4 versus 30.2 +/- 1.4, respectively), aggravation of right ventricular hypertrophy (P < 0.05), and muscularization of distal vessels (P < 0.01). Lung factor VIII, CD31 immunostaining, as well as eNOS expression were significantly increased after exposure to hypoxia in Ad.CO1-pretreated controls, but decreased in both normoxic and hypoxic animals after treatment with Ad.K3. The results show that inhibition of hypoxia-induced stimulation of lung angiogenic processes aggravates development of hypoxic PH. This suggests that endogenous lung angiogenesis counteracts development of hypoxic PH.
Am J Respir Cell Mol Biol 2003 Oct
PMID:Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice. 1271 72


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