Investigation into the in vivo and in vitro effects of anti-angiogenic therapy on abdominal aortic aneurysms

Medical therapy to prevent abdominal aortic aneurysm (AAA) development and progression is not currently available. Angiogenesis and extracellular signal-related kinase (ERK) pathway are key modulators of matrix metallo proteinases (MMPs) during AAA formation. The aim of the study described in this thesis is to evaluate the effects of Sorafenib (a multikinase inhibitor with antiangiogenic and ERK inhibitory properties) on experimental AAAs, and its in-vitro equivalent, 5-Br SU6668, on co-cultures of human AAA smooth muscle cells (SMCs) with aortic endothelial cells (AECs).

To study in vivo effects, Apolipoprotein E knock out (ApoE-/-) mice were assigned to either 28 days of angiotensin-II (AngII) infusion alone (Group 1); AngII+Sorafenib from day-1 (Group 2); AngII+Sorafenib from day-10 (Group 3); or saline infusion (negative control, Group 4). Sorafenib reduced the development (Group-2 versus Group-1, P=0.001) and progression (Group-3 versus Group-1, P=0.0002) of AAAs. Mice treated with Sorafenib resulted in greater preservation of elastin and collagen layers within their aortic wall and significantly reduced angiogenesis (CD34 cells), inflammatory infiltrates, expression of pro-angiogenic genes (Raf1, Nras, Pi3k, Akt3, Vegf, Il6) and MMP-2 and -9 protein expressions (all P<0.05).

In-vitro, 5-Br SU6668 prevented ERK phosphorylation and reduced gene expression of pro-angiogenic cytokine {Interleukin -6 (IL-6), P=0.04} and protein levels of pro-angiogenic peptides {Monocyte Chemotactic Protein-1(MCP-1) and MMP2, P<0.05) in co-cultures of human AAA SMCs and AECs.

Targeting the angiogenic pathway via inhibition of ERK phosphorylation is a potential therapy to prevent AAA growth. Whether anti-angiogenic therapy reduces human AAA development and growth warrants further investigation.