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Wulf D Ito

Publications and source records attributed to Wulf D Ito.

9 recordsLinked to original sources
PubMed2006

Carcinoembryonic antigen-related cell adhesion molecule 1 modulates vascular remodeling in vitro and in vivo.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cellular adhesion molecule of the Ig superfamily, is associated with early stages of angiogenesis. In vitro, CEACAM1 regulates proliferation, migration, and differentiation of murine endothelial cells. To prove that CEACAM1 is functionally involved in the regulation of vascular remodeling in vivo, we analyzed 2 different genetic models: in Ceacam1-/- mice, the Ceacam1 gene was deleted systemically, and in CEACAM1(endo+) mice, CEACAM1 was overexpressed under the control of the endothelial cell-specific promoter of the Tie2 receptor tyrosine kinase. In Matrigel plug assays, Ceacam1-/- mice failed to establish new capillaries whereas in CEACAM1(endo+) mice the implants were vascularized extensively. After induction of hind limb ischemia by femoral artery ligation, Ceacam1-/- mice showed significantly reduced growth of arterioles and collateral blood flow compared with their WT littermates. In agreement with a causal role of CEACAM1 in vascular remodeling, CEACAM1(endo+) mice exhibited an increase in revascularization and collateral blood flow after arterial occlusion. Our findings indicate that CEACAM1 expression is important for the establishment of newly formed vessels in vivo. Hence CEACAM1 could be a future target for therapeutic manipulation of angiogenesis in disease.

Animals↗
PubMed2006

Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase.

BACKGROUND: Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase (MPO) has emerged as an important mechanistic participant in impaired vasomotor function. MPO binds to and transcytoses endothelial cells in a glycosaminoglycan-dependent manner, and MPO binding to the vessel wall is a prerequisite for MPO-dependent oxidation of endothelium-derived nitric oxide (NO) and impairment of endothelial function in animal models. In the present study, we investigated whether heparin mobilizes MPO from vascular compartments in humans and defined whether this translates into increased vascular NO bioavailability and function. METHODS AND RESULTS: Plasma MPO levels before and after heparin administration were assessed by ELISA in 109 patients undergoing coronary angiography. Whereas baseline plasma MPO levels did not differ between patients with or without angiographically detectable coronary artery disease (CAD), the increase in MPO plasma content on bolus heparin administration was higher in patients with CAD (P=0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation (P<0.01) and by acetylcholine-induced changes in forearm blood flow (P<0.01). The extent of heparin-induced MPO release was correlated with improvement in endothelial function (r=0.69, P<0.01). Moreover, and consistent with this tenet, ex vivo heparin treatment of extracellular matrix proteins, cultured endothelial cells, and saphenous vein graft specimens from CAD patients decreased MPO burden. CONCLUSIONS: Mobilization of vessel-associated MPO may represent an important mechanism by which heparins exert antiinflammatory effects and increase vascular NO bioavailability. These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans.

Aged↗
PubMed2006

Vascular wall resident progenitor cells: a source for postnatal vasculogenesis.

Here, we report the existence of endothelial precursor (EPC) and stem cells in a distinct zone of the vascular wall that are capable to differentiate into mature endothelial cells, hematopoietic and local immune cells, such as macrophages. This zone has been identified to be localized between smooth muscle and adventitial layer of human adult vascular wall. It predominantly contains CD34-positive (+) but CD31-negative (-) cells, which also express VEGFR2 and TIE2. Only few cells in this zone of the vascular wall are positive for CD45. In a ring assay using the fragments of human internal thoracic artery (HITA), we show here that the CD34+ cells of the HITA-wall form capillary sprouts ex vivo and are apparently recruited for capillary formation by tumor cells. New vessels formed by these vascular wall resident EPCs express markers for angiogenically activated endothelial cells, such as CEACAM1, and also for mature endothelial cells, such as VE-cadherin or occludin. Vascular wall areas containing EPCs are found in large and middle sized arteries and veins of all organs studied here. These data suggest the existence of a ;vasculogenic zone' in the wall of adult human blood vessels, which may serve as a source for progenitor cells for postnatal vasculogenesis, contributing to tumor vascularization and local immune response.

Adult↗
PubMed2004

Tissue resident cells play a dominant role in arteriogenesis and concomitant macrophage accumulation.

Collateral growth is characterized by macrophage accumulation, suggesting an important role of circulating cells. To study origin and function of macrophages during arteriogenesis, we related the extent of macrophage accumulation to vascular proliferation and investigated the fate of fluorescently (CMFDA) labeled blood cells that were injected at the time of femoral artery occlusion. The effect of bone marrow depletion via cyclophosphamide before femoral artery occlusion on collateral proliferation and macrophage accumulation was studied, and we looked for the presence of bone marrow-derived stem cells in the vicinity of growing collateral vessels. Finally, we investigated the arteriogenic effect of macrophage activation via MCP-1 in bone marrow-depleted animals. Maximal macrophage accumulation occurred during the first 3 days after femoral artery occlusion and paralleled the extent of vascular proliferation. Fluorescently labeled leukocytes homed to spleen and wound but they were absent in proliferating collateral arteries during maximal macrophage accumulation. Depletion of circulating cells did neither affect macrophage accumulation nor collateral growth. Staining of monocyte-depleted animals for BrdUrd and ED2, alphaSMA, or VE-Cadherin demonstrated local proliferation of macrophages and vascular cells, whereas C-Kit, SSEA1, or Thy1-positive bone marrow-derived stem cells were not detectable. Enhancement of macrophage accumulation via MCP-1 was independent of circulating monocytes and promoted arteriogenesis in the absence of direct effects on vascular cells. We propose that the initial phase of vascular growth is characterized by local proliferation of tissue resident precursors rather than by migration of blood born cells. The full text of this article is available online at http://circres.ahajournals.org.

Actins↗
PubMed2003

Proteome analysis of migrating versus nonmigrating rat heart endothelial cells reveals distinct expression patterns.

Migration of endothelial cells plays an important role during angiogenesis and the late remodeling phase of arteriogenesis. To investigate mechanisms responsible for cell migration, the authors subcloned a rat heart endothelial cell line (RHE) into a migrating and a nonmigrating cell line (RHE-A and RHE-neg, respectively). Both cell lines form cobblestone patterns in confluent cultures similar to the originating cell line, but RHE-neg cells grow in dense cell islets of several layers whereas RHE-A cells grow in a less dense monolayer. Both cell lines show the same expression pattern of known endothelial cell surface antigens (e.g., FIK-1). The authors used two-dimensional gel electrophoresis technique to look for differentially regulated proteins with possible functional importance for cell migration. The analysis of the cytosolic fraction as well as the membrane fraction revealed differences in the protein expression patterns of RHE-neg and RHE-A cells. Regulated spots were isolated and analyzed by mass spectrometry (MS/MS technique), leading to the identification of proteins potentially responsible for endothelial cell migration, e.g., the intermediate filament vimentin that was exclusively expressed in RHE-A cells. The authors thus have generated a reproducible model that allows the analysis of the proteome responsible for endothelial cell migration.

Animals↗
PubMed2003

Biopanning of single-chain antibodies expressing phages reveals distinct expression patterns of angiogenic and arteriogenic vessels.

"Therapeutic angiogenesis" requires targeted delivery of growth factors for maximal benefit and limitation of potential hazards such as enhancement of tumor or plaque angiogenesis. Physiological distinctions between angiogenesis and collateral growth suggest the possibility of targeting selectively collateral endothelium. This article describes the generation of collateral-targeting single-chain antibodies (scFv). Membrane preparations of growing collateral arteries from rats were used to produce collateral-targeting antibodies (CTAs) via immunization of mice. ScFv were generated from CTA-producing hybridoma and cloned into the pV gene of M13 phages. Phages expressing collateral-targeting scFv (CT scFv) were selected via repeated exposure to activated collateral arteries followed by reamplification. CT scFv could specifically be amplified, selected, and sequenced. Phages expressing CT scFv bound selectively to proliferating collateral vessels as identified by positive Polycyclic Nuclear Antigen (PCNA) staining and homed specifically to collateral endothelium after in vivo injection but bound neither to control vessels nor to tumor vessels. This study reveals major differences between angiogenic and collateral endothelium and delivers a tool that will allow the stimulation of collateral growth without promoting tumor or plaque angiogenesis.

Amino Acid Sequence↗
PubMed2003

Tissue macrophages: "satellite cells" for growing collateral vessels? A hypothesis.

It has been demonstrated in several studies that collateral growth is associated with accumulation of macrophages around proliferating vessel. Macrophages are known to secrete vascular growth factors and metalloproteinases. Both are necessary for the development of a proper vasculature. Recent studies suggest that certain subpopulations of macrophages are also capable of transdifferentiating into vascular cells. There are good reasons to assume that shear force rises dramatically in preexisting arteriolar shunts after occlusion of the main supplying vessel. Based upon these two findings it was hypothesized that high shear forces lead to homing of circulating monocytes to the growing collateral artery. The majority of studies, however, indicate that monocytes home under low shear force conditions. Our own observations in monocyte depleted animals suggest that proliferation and transdifferentiation of tissue macrophages occurs locally in growing collateral vessels and is independent of circulating cells. We thus propose that local proliferation and transdifferentiation of tissue macrophages rather than homing of circulating monocytes play a major role in arteriogenesis.

Arteries↗
PubMed2002

Collateral arteries grow from preexisting anastomoses in the rat hindlimb.

Previous findings have suggested that collateral arteries grow from preexisting arteriolar anastomoses ("arteriogenesis"). To investigate whether collateral growth occurs without preceding angiogenesis, we obtained vascular casts and postmortem angiographies 3, 7, and 21 days after unilateral femoral artery occlusion in the rat. Proliferation kinetics were determined after 5'-bromo-2'-desoxyuridin infusion. A preexisting anastomosis was identified. Proliferation of this vessel began 24 h after femoral artery occlusion, increased maximally during the first 3 days, and reached 60% at day 7. Cell division was restricted to preexisting anastomoses and occurred neither in directly neighboring arterial vessels nor in capillaries. Collateral vessels doubled their diameter within 7 days and assumed a typical corkscrew appearance (increase of length: 21%). After 7 days of occlusion, we measured a further increase of length (14%) but no proliferation or increase of diameter. We conclude that arteriogenesis is a biphasic process involving rapid proliferation of preexisting arteriolar shunts followed by pronounced remodeling processes. Arteriogenesis occurs independently of angiogenesis and denotes a separate entity of vascular proliferation.

Angiography↗