30
this type of advance. The EC tubulogenic signaling cascade is highly complex and
needs to be investigated in considerably more detail. A fundamental question, which
remains unanswered, is what allows ECs to form lumen and tubes, while cells such
as pericytes and fibroblasts cannot perform this function. In attempts to create the
EC lineage from any other cell type, it is essential to determine whether the cells can
form tubes in a 3D matrix environment, which is one of primary functional roles of
ECs. It is likely that a detailed understanding of these processes will lead to important new opportunities to treat disease. Many of the most important acute and
chronic diseases include a major component involving the dysfunction or breakdown of the vasculature (e.g., cancer, diabetes, tissue fibrosis, hypertension, atherosclerosis). Another important concept that needs to be stressed is that molecules
(growth factors, ECM, receptors, MMPs) and downstream signaling molecules
work together (i.e., multiprotein complexes), and it is critical to understand how
such molecules and pathways temporally coordinate to control the observed biological responses. The single molecule analysis and approach that is inherent to
many studies can be quite misleading in terms of our understanding of complex
biological events. Systems approaches (i.e., RNAseq, non-coding RNA regulation,
and proteomics analyzing protein-protein interactions with identification of key
phosphorylation sites) are important directions in future work to identify new critical regulators of the pathways that control vascularization responses and to assess
how these are altered in the context of vascular disease.
Acknowledgments This work was supported by NIH grants HL126518, HL128584, and
HL136139 to G.E. Davis.
References
1. Adams, R. H., & Alitalo, K. (2007). Molecular regulation of angiogenesis and lymphangiogenesis. Nature Reviews, 8, 464–478.
2. Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., & Cheresh, D. A. (2003). Role of Raf in
vascular protection from distinct apoptotic stimuli. Science (New York, N.Y.), 301, 94–96.
3. Aplin, A. C., Fogel, E., Zorzi, P., & Nicosia, R. F. (2008). The aortic ring model of angiogenesis. Methods in Enzymology, 443, 119–136.
4. Aplin, A. C., Zhu, W. H., Fogel, E., & Nicosia, R. F. (2009). Vascular regression and survival
are differentially regulated by MT1-MMP and TIMPs in the aortic ring model of angiogenesis. American Journal of Physiology, 297, C471–C480.
5. Armulik, A., Abramsson, A., & Betsholtz, C. (2005). Endothelial/pericyte interactions.
Circulation Research, 97, 512–523.
6. Astrof, S., Crowley, D., & Hynes, R. O. (2007). Multiple cardiovascular defects caused by the
absence of alternatively spliced segments of fibronectin. Developmental Biology, 311, 11–24.
7. Baker, A. H., Edwards, D. R., & Murphy, G. (2002). Metalloproteinase inhibitors: Biological
actions and therapeutic opportunities. Journal of Cell Science, 115, 3719–3727.
8. Bayless, K. J., & Davis, G. E. (2002). The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices. Journal of Cell Science,
115, 1123–1136.
G. E. Davis
this type of advance. The EC tubulogenic signaling cascade is highly complex and
needs to be investigated in considerably more detail. A fundamental question, which
remains unanswered, is what allows ECs to form lumen and tubes, while cells such
as pericytes and fibroblasts cannot perform this function. In attempts to create the
EC lineage from any other cell type, it is essential to determine whether the cells can
form tubes in a 3D matrix environment, which is one of primary functional roles of
ECs. It is likely that a detailed understanding of these processes will lead to important new opportunities to treat disease. Many of the most important acute and
chronic diseases include a major component involving the dysfunction or breakdown of the vasculature (e.g., cancer, diabetes, tissue fibrosis, hypertension, atherosclerosis). Another important concept that needs to be stressed is that molecules
(growth factors, ECM, receptors, MMPs) and downstream signaling molecules
work together (i.e., multiprotein complexes), and it is critical to understand how
such molecules and pathways temporally coordinate to control the observed biological responses. The single molecule analysis and approach that is inherent to
many studies can be quite misleading in terms of our understanding of complex
biological events. Systems approaches (i.e., RNAseq, non-coding RNA regulation,
and proteomics analyzing protein-protein interactions with identification of key
phosphorylation sites) are important directions in future work to identify new critical regulators of the pathways that control vascularization responses and to assess
how these are altered in the context of vascular disease.
Acknowledgments This work was supported by NIH grants HL126518, HL128584, and
HL136139 to G.E. Davis.
References
1. Adams, R. H., & Alitalo, K. (2007). Molecular regulation of angiogenesis and lymphangiogenesis. Nature Reviews, 8, 464–478.
2. Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., & Cheresh, D. A. (2003). Role of Raf in
vascular protection from distinct apoptotic stimuli. Science (New York, N.Y.), 301, 94–96.
3. Aplin, A. C., Fogel, E., Zorzi, P., & Nicosia, R. F. (2008). The aortic ring model of angiogenesis. Methods in Enzymology, 443, 119–136.
4. Aplin, A. C., Zhu, W. H., Fogel, E., & Nicosia, R. F. (2009). Vascular regression and survival
are differentially regulated by MT1-MMP and TIMPs in the aortic ring model of angiogenesis. American Journal of Physiology, 297, C471–C480.
5. Armulik, A., Abramsson, A., & Betsholtz, C. (2005). Endothelial/pericyte interactions.
Circulation Research, 97, 512–523.
6. Astrof, S., Crowley, D., & Hynes, R. O. (2007). Multiple cardiovascular defects caused by the
absence of alternatively spliced segments of fibronectin. Developmental Biology, 311, 11–24.
7. Baker, A. H., Edwards, D. R., & Murphy, G. (2002). Metalloproteinase inhibitors: Biological
actions and therapeutic opportunities. Journal of Cell Science, 115, 3719–3727.
8. Bayless, K. J., & Davis, G. E. (2002). The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices. Journal of Cell Science,
115, 1123–1136.
G. E. Davis