Angiogenesis is the process by which existing blood vessels sprout to form new vessels. During development and some physiological events in the adult, angiogenesis occurs as a controlled series of events leading to vascular remodeling that supports changing tissue requirements. A host of pro- and anti-angiogenic factors work in a balance to allow initial sprouting and invasion, subsequent pruning and remodeling, and finally maturation and survival. However, in pathological situations such as cancer, the same angiogenic signaling pathways are induced and exploited, typically resulting in poorly organized vessels with leaky and tortuous properties. Angiogenesis is ultimately controlled by a balance of pro- and anti-angiogenic factors that regulate the recruitment and activation of stromal and vascular cells. Here, we have identified a novel pathway in which a pro-angiogenic microRNA disrupts the expression of an anti-angiogenic signaling molecule. MicroRNAs are short nucleotide sequences that have the ability to block expression of target genes. We have identified miR-132 as a microRNA which is not expressed in stable quiescent vessels, but which is upregulated in angiogenic tissues and in endothelial cells stimulated with growth factors. Expression of miR-132 is sufficient to drive vascular sprouting and proliferation in the absence of growth factors, whereas inhibition of miR-132 blocks growth factor-induced angiogenesis. Thus, we have shown that miR-132 functions as a pro-angiogenic factor which can activate endothelial cells. Furthermore, we have identified a RasGAP family member, p120RasGAP, as a primary target gene of miR-132.
In Aim 1, we will evaluate the contribution of p120RasGAP activity to Ras-dependent and Ras-independent signaling, and determine whether the expression of p120RasGAP may be modulated by additional miRs during angiogenesis.
In Aim 2, we will characterize the expression and role of RasGAP homologs in endothelial cells, and identify whether these may also be subject to miR regulation during angiogenesis. The long-term objective and clinical application of this work is to evaluate the use of anti-miRs targeting RasGAP family members as anti-angiogenic therapies for diseases that are exacerbated by vascular proliferation (Aim 3). Together, these studies will provide insight into the role of RasGAPs during angiogenesis and establish a molecular basis to support the development of anti-miR therapy as an anti-angiogenic strategy for patients with vascular proliferative disease.
Angiogenesis is the process by which new blood vessels are formed by sprouting from the existing vasculature. We have identified a novel vascular stabilization factor that is expressed on normal blood vessels, but lost on the activated blood vessels within angiogenic tissues. A thorough understanding of how this factor determines whether a blood vessel remains quiescent or becomes activated will allow development of new therapies that can limit angiogenesis associated with cancer or vascular proliferative disorders.
|Westenskow, Peter D; Kurihara, Toshihide; Aguilar, Edith et al. (2013) Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. J Clin Invest 123:4900-8|
|Lim, Ssang-Taek; Miller, Nichol L G; Chen, Xiao Lei et al. (2012) Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression. J Cell Biol 197:907-19|
|Scheppke, Lea; Murphy, Eric A; Zarpellon, Alessandro et al. (2012) Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to the endothelial basement membrane. Blood 119:2149-58|
|Chen, Xiao Lei; Nam, Ju-Ock; Jean, Christine et al. (2012) VEGF-induced vascular permeability is mediated by FAK. Dev Cell 22:146-57|
|Mielgo, Ainhoa; Seguin, Laetitia; Huang, Miller et al. (2011) A MEK-independent role for CRAF in mitosis and tumor progression. Nat Med 17:1641-5|
|Anand, Sudarshan; Cheresh, David A (2011) MicroRNA-mediated regulation of the angiogenic switch. Curr Opin Hematol 18:171-6|
|Weis, Sara M; Cheresh, David A (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359-70|