Abdominal aorta aneurysm (AAA) is a common and lethal disease of adult Americans. Progressive AAA enlargement, over the course of months to years, leads to ever-increasing risk of sudden death from catastrophic rupture. Currently, rupture can only be prevented by timely surgical repair, which carries considerable morbidity and/or requirements for ongoing surveillance and periodic re-intervention. Prior attempts to identify specific mediator or pathway targets for medical intervention have not translated to effective clinical therapies. Although medial and adventitial neovessel formation (mural angiogenesis) is well recognized in human and experimental AAA, the role of angiogenesis in AAA pathogenesis has not been studied. Based on our preliminary findings that VEGF-A-producing cells were increased in aneurysmal aortae, and that inhibition of VEGF signaling by either soluble VEGFR-2 or VEGFR inhibitor sunitinib significantly suppressed AAA progression, it is our fundamental hypothesis that VEGF-A-mediated mural angiogenesis is a critical and rate-limiting factor in aortic aneurysm pathogenesis, and that manipulation of VEGF signaling will modulate progression and regression of experimental aneurysms. To pursue this hypothesis, we propose the following Specific Aims: 1. Determine cellular origin and magnitude of aortic VEGF-A production in AAA disease. 2. Define the role of VEGF-A signaling in AAA disease progression. 3. Evaluate ability of FDA-approved VEGFR inhibitors to stabilize or regress AAA. Using the well-established mouse aortic elastase infusion model of human AAA disease, we will employ immunostaining, confocal imaging and ELISA assays to analyze the kinetics and cellular origins of VEGF-A expression during aneurysm development. We will use multiple genetic tools to block VEGF-A both in a systemic and cell-specific manner to define the role of VEGF-A-driven angiogenesis in AAA pathogenesis. We will further evaluate the effects of FDA-approved anti-angiogenesis drugs (sunitinib and sorafenib) on the progression and regression of AAA. Confirming the pathogenetic significance of VEGF-A-driven angiogenesis in AAA disease will facilitate the rapid translation of emerging anti-angiogenesis therapeutic strategies to effective non-surgical methods of aneurysm suppression.
Abdominal aortic aneurysm (AAA) is a common, morbid and frequently lethal disease. In the course of investigating how mural angiogenesis influences aneurysm progression, we hope to discover novel treatment strategies to limit progression of early AAA disease and, in the process, improve the health and well-being of millions of Americans.
|Wang, Wei; Xu, Baohui; Xuan, Haojun et al. (2018) Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease. J Vasc Surg 68:1538-1550.e2|
|Xuan, Haojun; Xu, Baohui; Wang, Wei et al. (2018) Inhibition or deletion of angiotensin II type 1 receptor suppresses elastase-induced experimental abdominal aortic aneurysms. J Vasc Surg 67:573-584.e2|
|Fujimura, Naoki; Xiong, Jiang; Kettler, Ellen B et al. (2016) Metformin treatment status and abdominal aortic aneurysm disease progression. J Vasc Surg 64:46-54.e8|
|Fujimura, Naoki; Xu, Baohui; Dalman, Jackson et al. (2015) CCR2 inhibition sequesters multiple subsets of leukocytes in the bone marrow. Sci Rep 5:11664|
|Kortekaas, Kim E; Meijer, C Arnoud; Hinnen, Jan Willem et al. (2014) ACE inhibitors potently reduce vascular inflammation, results of an open proof-of-concept study in the abdominal aortic aneurysm. PLoS One 9:e111952|
|Rouer, M; Xu, B H; Xuan, H J et al. (2014) Rapamycin limits the growth of established experimental abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 47:493-500|
|Iida, Yasunori; Xu, Baohui; Xuan, Haojun et al. (2013) Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression. Arterioscler Thromb Vasc Biol 33:718-26|
|Iida, Yasunori; Xu, Baohui; Schultz, Geoffrey M et al. (2012) Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms. PLoS One 7:e49642|