The role of angiopoietin-2 in experimental abdominal aortic aneurysm development

Yu, Hongyou (2015) The role of angiopoietin-2 in experimental abdominal aortic aneurysm development. PhD thesis, James Cook University.

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Abstract

Abdominal aortic aneurysm (AAA) is an abnormal dilatation of the aorta that is permanent and progressive. The most severe consequence of AAA is rupture, and as the aorta is the main vessel leading away from heart, it can be fatal. AAA affects around 2-5% of men over the age of 65. Only surgery can currently repair AAA. No other efficient clinical interventions currently exist to prevent AAA from progression to rupture, due to the lack of understanding the pathogenesis of AAA. Therefore, understanding the molecular and cellular mechanisms that lead to the development of AAA is critical for identifying strategies to interrupt disease progression before it leads to clinical consequences. Recently, Golledge and colleagues reported that serum angiopoietin-2 (Angpt2) was elevated in men with AAA, and associated with an increased risk of cardiovascular mortality in older men. This suggests that Angpt2 could play a role in AAA development and be a potential target for clinical treatment to limit AAA progression and rupture.

Angpt2 is a member of angiopoietin family that regulates angiogenesis and inflammation via its receptor Tie2. Angpt2 is originally identified as an antagonist of Tie2, and it subsequently induces endothelial cell activation, thereby facilitating angiogenesis and inflammation. However, Angpt2 has also been demonstrated to be an agonist of Tie2 in a context dependent manner both in vitro and in vivo. Exogenous Angpt2 has been reported to reduce atherosclerosis development, angiogenesis within the tumour, and cellular infiltration in the ongoing inflammation. Angiogenesis and inflammation have been implicated in aortic aneurysm and in the development of atherosclerosis. In this thesis, I examine the role of Angpt2 in aortic aneurysm and atherosclerosis development, using the angiotensin II (AngII) infused mouse model in apolipoprotein E-deficient (ApoE⁻/⁻) mice.

Six-month-old male ApoE⁻/⁻ mice were infused with AngII, in order to induce aortic aneurysm and the progression of atherosclerosis. Human Fc-protein (control), recombinant Angpt2 (rAngpt2), or Angpt2-Tie2 interacting inhibitor (L1-7) was subcutaneously administered to mice for 14 days. rAngpt2 administration significantly inhibited AngII induced suprarenal aortic expansion (p=0.002) and atherosclerosis within the aortic arch (p=0.017). rAngpt2 administration also protected AAA from rupture (p=0.034). These effects were blood pressure and plasma lipoprotein independent. However, L1-7 administration did not alter AngII-induced AAA development and rupture and atherosclerosis.

By assessing inflammation, it was found that mice receiving rAngpt2 had significant Tie2 activation (p=0.026) and less MOMA-2 (p=0.004) positive immunostaining area within the aortic tissue, compared with mice receiving control protein, suggesting reduced inflammation. Consistently, in the mice receiving rAngpt2, it was found that there was less monocyte chemoattractant protein-1 (MCP-1) expression (p=0.004), within the aortic tissue. The plasma concentration of MCP-1 and interleukin-6 (IL-6) were significantly lower (p=0.011 and p=0.013 respectively). In mice receiving rAngpt2 for 14 days, Ly6Cʰⁱ inflammatory monocytes were lower within the peripheral blood (p=0.003), but increased within the bone marrow (p=0.019). At early stage of AngII infusion (5 days), rAngpt2 administration resulted in the retention of Ly6Cʰⁱ inflammatory monocytes and the elevation of neutrophils recycling in the spleen. These results suggest that exogenous Angpt2 administration reduced AngII-induced inflammation within the aortic tissue in ApoE⁻/⁻ mice.

By assessing the angiogenesis, it was found that there was a smaller CD31 (p=0.002) positive immunostaining area and no difference in vascular endothelial growth factor expression within the aortic tissue from mice receiving rAngpt2 compared with mice receiving control protein. There was no difference in Akt/eNOS and Erk signalling pathway activation within the aortic tissue between the two groups of mice. These results suggest that mice receiving exogenous Angpt2 had limited angiogenesis within the aortic tissue in the AngII-infused ApoE⁻/⁻ mice.

It was therefore concluded that exogenous Angpt2 administration attenuated AngII-induced aortic aneurysm and atherosclerosis in ApoE⁻/⁻ mice associated with reduced aortic inflammation and angiogenesis. Endogenous Angpt2-Tie2 interacting induced Tie2 deactivation was not required for AAA and atherosclerosis development in this AngII infusion mouse model.

Item ID: 46025
Item Type: Thesis (PhD)
Keywords: abdominal aneurysm; abdominal aortic aneurysm; angiopoietin-2; angiopoietin-II; cardiovascular diseases; cardiovascular system; dilatation; in vitro; neovascularization; ruptures
Date Deposited: 11 Oct 2016 04:40
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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