Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress–specific manner

Abstract

Although the response of endothelial cells to the disturbed blood flow in the vicinity of atherosclerotic lesions is known to be distinct from that elicited by nonatherogenic laminar flow, the mechanisms involved are poorly understood. Our initial studies confirmed that expression of the endothelial receptor tyrosine kinase Tie1 was evident at regions of atherogenic flow in mature animals. We therefore hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Consistent with this, we found that Tie1 +/-mice bred to the apoE-deficient background displayed a 35% reduction in atherosclerosis relative to Tie1 +/+ ;Apoe -/-mice. Since deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we used conditional and inducible mutagenesis to study the effect of endothelial-specific Tie1 attenuation on atherogenesis in Apoe -/-mice and found a dose-dependent decrease in atherosclerotic lesions. Analysis of primary aortic endothelial cells indicated that atheroprotective laminar flow decreased Tie1 expression in vitro. Attenuation of Tie1 was associated with an increase in eNOS expression and Tie2 phosphorylation. In addition, Tie1 attenuation increased IkBα expression while decreasing ICAM levels. In summary, we have found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression. Therefore, Tie1 may play a novel proinflammatory role in atherosclerosis.

Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

“…Microarray analysis of HUVEC gene expression under static and 2 Pa laminar shear stress showed CLEC14A and ROBO4 were markedly upregulated (significant false discovery rate of o12% and o1% respectively) in the absence of shear stress. Real-time PCR analysis confirmed the predicted downregulation of CLEC14A and ROBO4 expression (Figure 9a) in HUVEC exposed to 2 Pa of shear stress for 24 h. TIE1 is a validated marker of reduced shear stress at the endothelial surface (Chen-Konak et al, 2003;Porrat et al, 2004;Woo et al, 2011). Double immunofluorescence staining of TIE1 and CLEC14A showed that they co-localised on tumor vessels (Figure 9b).…”

Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy

“…The overall healthy condition of the Tie1-deleted mice is consistent with the conclusion that their possible vascular changes would have to be relatively subtle. Furthermore, recent experiments have shown that atherosclerosis is inhibited by partial Tie1 deletion (20), which argues that decreased Tie1 function might be beneficial not only in cancer, but also in atherosclerosis patients. Thus, our present findings elucidate a previously unknown regulatory system for angiogenesis and propose Tie1 as a potential new target for anti-angiogenic therapy that potentially holds clinical relevance now, more than 20 years after its isolation (59), when we first suggestedbased on its enhanced expression pattern in the tumor vasculature (19) -the possible involvement for this interesting receptor in tumorigenesis and other angiogenesis-dependent diseases, such as diabetic retinopathy, atherosclerosis, and arthritis.…”

“…Tie1 expression is increased in adults during wound healing, ovarian follicle maturation, and tumor angiogenesis (11,19). According to Woo et al, postnatal loss of 40%-80% of Tie1 did not result in obvious pathology, but instead conferred an atheroprotective effect, in a murine model (20).…”

“…Endothelial Tie1 has been suggested to play a role in inflammation, and inflammatory cells regulate tumor angiogenesis and growth (20,26). Therefore, we investigated whether Tie1 deletion affects endothelial expression of leukocyte adhesion receptors or leukocyte recruitment to the tumor stroma.…”

TIE-ing off atherosclerosis

“…1 Now the team plans to study the mechanism underlying the therapeutic effect. The findings could represent a new indication for sanofi-aventis Group, which has licensed at least two therapies targeting tyrosine kinase receptor proteins in cancer and wound healing.…”