Macrophages in collateral arteriogenesis.

Arteriosclerotic vascular disease is the most common cause of death and a major cause of disability in the developed world. Adverse outcomes of arteriosclerotic vascular disease are related to consequences of tissue ischemia and necrosis affecting the heart, brain, limbs, and other organs. Collateral artery growth or arteriogenesis occurs naturally and can help restore perfusion to ischemic tissues.

Continuous endothelial cell activation increases angiogenesis: evidence for the direct role of endothelium linking angiogenesis and inflammation.

There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including the induction of aberrant angiogenesis. While leukocytes have been described as mediators of inflammation-associated angiogenesis, the effects of direct chronic endothelial activation have not been addressed in this context. Using an uncleavable mutant of the transmembrane form of tumor necrosis factor-alpha (TNF-alpha), we have established models of stable TNF-alpha expression in endothelial cells in vitro and in transgenic mice in vivo.

Impact of mouse strain differences in innate hindlimb collateral vasculature.

Objective: To assess the importance of genetic background for collateral artery development.

Methods And Results: C57BL/6, BALB/c and 129S2/Sv mice were studied after femoral artery ligation by laser Doppler imaging, visible light oximetry, time-of-flight-magnetic resonance imaging, and treadmill testing; C57BL/6 and BALB/c also underwent electron paramagnetic resonance (EPR) oximetry, x-ray angiography, and histology. C57BL/6 had the least initial distal ischemia and most complete recovery.

Delayed arteriogenesis in hypercholesterolemic mice.

Background: Hypercholesterolemia has been reported to inhibit ischemia-induced angiogenesis. To address its effects on arteriogenesis, we investigated arterial growth in hypercholesterolemic low-density lipoprotein receptor(-/-)/ApoB-48(-/-) (HCE) mice.

Methods And Results: The extent and the time course of arteriogenesis after femoral artery ligation was evaluated in HCE and strain-matched control mice.

Synthesis of anticoagulantly active heparan sulfate proteoglycans by glomerular epithelial cells involves multiple 3-O-sulfotransferase isoforms and a limiting precursor pool.

Endothelial and other select cell types synthesize a subpopulation of heparan sulfate (HS) proteoglycans (HSPGs), anticoagulant HSPGs (aHSPGs) that bear aHS-HS chains with the cognate 3-O-sulfated pentasaccharide motif that can bind and activate anti-thrombin (AT). Endothelial cells regulate aHSPG production by limiting levels of HS 3-O-sulfotransferase-1 (3-OST-1), which modifies a non-limiting pool of aHS-precursors. By probing kidney cryosections with (125)I-AT and fluorescently tagged AT we found that the glomerular basement membrane contains aHSPGs, with the staining pattern implicating synthesis by glomerular epithelial cells (GECs).

Time-of-flight quantitative measurements of blood flow in mouse hindlimbs.

Purpose: To evaluate the feasibility of using time-of-flight (TOF) imaging to directly measure hindlimb blood flow in a mouse model of peripheral vascular disease.

Materials And Methods: Four tubes were imaged simultaneously (diameters = 0.39 mm, 0.

Magnetic resonance angiography of collateral vessels in a murine femoral artery ligation model.

The in vivo detection of growing collateral vessels following arterial occlusion is difficult in small animals. We have addressed the feasibility of performing high resolution time-of-flight angiograms to monitor the growth of collateral vessels after femoral artery occlusion in mice. We will also present a low-pass quadrature birdcage coil construction with a sufficient signal-to-noise ratio to produce high resolution.

Thromboxane A2 receptor agonists antagonize the proangiogenic effects of fibroblast growth factor-2: role of receptor internalization, thrombospondin-1, and alpha(v)beta3.

Thromboxane (TX) A2 is released from multiple cell types and is a prime mediator of the pathogenesis of many vascular events, including angiogenesis. Endothelial cells express TXA2 receptors (TP) but the effects of TP stimulation on angiogenesis remain controversial. In this study, we show that stimulation of endothelial cell TP impairs ligand-induced FGF receptor internalization and consequently abrogates FGF-2-induced endothelial cell migration in vitro and angiogenesis in vivo.

Collateral artery growth (arteriogenesis) after experimental arterial occlusion is impaired in mice lacking CC-chemokine receptor-2.

Arteriogenesis has been associated with the presence of monocytes/macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein-1 (MCP-1, or CCL2 in the new nomenclature) to the CCR2-chemokine receptor on macrophages. To determine whether the CCL2-CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth.

Inhibition of collateral artery growth by mibefradil: possible role of volume-regulated chloride channels.

Endothelial cell swelling is one of the earliest hallmarks of arteriogenesis, the growth and maturation of collaterals. Mibefradil was found to block endothelial Cl(-) channels that control the volume of endothelial cells. Thus the authors investigated whether the blockade of volume-controlling endothelial cell channels would translate into an inhibition of arteriogenesis.

Bone marrow-derived cells do not incorporate into the adult growing vasculature.

Bone marrow-Derived cells have been proposed to form new vessels or at least incorporate into growing vessels in adult organisms under certain physiological and pathological conditions. We investigated whether bone marrow-Derived cells incorporate into vessels using mouse models of hindlimb ischemia (arteriogenesis and angiogenesis) and tumor growth. C57BL/6 wild-type mice were lethally irradiated and transplanted with bone marrow cells from littermates expressing enhanced green fluorescent protein (GFP).

Participation of bone marrow-derived cells in long-term repair processes after experimental stroke.

Bone marrow-derived cells participate in remodeling processes of many ischemia-associated diseases, which has raised hopes for the use of bone marrow as a source for cell-based therapeutic approaches. To study the participation of bone marrow-derived cells in a stroke model, bone marrow from C57BL/6-TgN(ACTbEGFP)1Osb mice that express green fluorescent protein (GFP) in all cells was transplanted into C57BL/6J mice. The recipient mice underwent permanent occlusion of the middle cerebral artery, and bone marrow-derived cells were tracked by fluorescence.

Arteriogenesis: the development and growth of collateral arteries.

In patients with atherosclerotic vascular diseases, collateral vessels bypassing major arterial obstructions have frequently been observed. This may explain why some patients remain without symptoms or signs of ischemia. The term "arteriogenesis" was introduced to differentiate the formation of collateral arteries from angiogenesis, which mainly occurs in the ischemic, collateral flow-dependent tissue.

Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice.

Gridlock (grl) is one of the first mutations characterized from the large zebrafish mutagenesis screens, and it results in an arterial (aortic) maturation defect, which was proposed to resemble aortic coarctation, a clinically important human malformation. While the grl mutation appears to be a hypomorph, grl knockdown experiments have shown even stronger effects on arterial development. We have generated a knockout of the murine Hey2 (gridlock) gene to analyze the mammalian phenotype.

Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice.

Unlabelled: The goal of this study was to examine the mechanisms of vascular growth that lead to the restoration of perfusion in a peripheral vascular disease model in mice. We monitored blood flow recovery and measured vascular growth in inbred strains of mice following femoral artery occlusion. Acute collateral blood flow to the hindlimb was lowest in Balb/C mice, causing intense ischemia, and showed a slower recovery (more than 21 days to 50% normal) than C57Bl/6 which had a 7-fold higher acute collateral flow and a fast recovery (3 days).