Arteriogenesis, the expansion of collateral arteries, is vital process for compensatory blood flow to tissues in response to vascular occlusions. In patients with peripheral arterial disease (PAD), arteriogenesis is crucial for overcoming limb ischemia, but for many, further treatment is required. In the United States alone, approximately 80,000 individuals lose limbs to this disease each year. Thus, it is critical to understand the mechanisms regulating arteriogenesis. Indirect evidence suggests that mitogen-activated protein kinase kinases 1 and 2 (MEK1 and 2) are involved in arteriogenesis, but this has not been directly tested. To do this, we used a mouse model of hindlimb ischemia, femoral artery ligation (FAL), treated with a specific allosteric MEK1 and 2 inhibitor (PD0325901). Whereas control mice showed increased myogenesis, angiogenesis, and arteriogenesis, mice dosed daily with PD0325901 failed to recover. In order to examine for any temporal regulation, mice were treated days 8 to 28 post surgery. Interestingly, mean arterial luminal area increased. In a complimentary experiment, mice were treated out to 7 days post surgery, treatment was stopped, and tissues were collected at day 28 post surgery. Although muscle tissue had recovered by this time, mean arterial luminal area remained low relative to controls, suggesting a critical window of MEK1 and 2 signaling being necessary for recovery. Surprisingly, results from MEK2–/– mice also fail to undergo arteriogenesis after surgery, indicating this effect may be specific to MEK2 alone. BrDU-injected mice co-stained with either CD31 or αSMA show that loss of MEK2 predominantly affects endothelial cells within the arteries. Lastly, equivalent results are shown in mice lacking tumor endothelial marker 8 (TEM8). These results indicate MEK2 activity is required for arteriogenesis, and show the first known physiological role for TEM8. In addition, the results have implications in the current use of MEK1 and 2 inhibitors for anti-cancer therapy, as these drugs may affect remodeling arteries. Our results also have potential implications for future therapies for PAD, as MEK2 activation after blockage could stimulate arterial growth, preventing the need for amputation.
|Commitee:||Alberts, Art, Chambers, Christopher, Kitajewski, Jan, Van Raamsdonk, Jeremy, Wang, Rong, Williams, Bart|
|School:||Van Andel Research Institute|
|School Location:||United States -- Michigan|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Biology, Genetics, Cellular biology|
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