Mechanical Forces and Molecular Signals Act through a Common Pathway to Control New Blood Vessel Growth
The Bottom Line
Researchers have identified a new signaling pathway that uses molecular signals and mechanical forces to control the formation of new blood vessels (angiogenesis) by endothelial cells (cells that make up the walls of blood vessels).
The Whole Story
The growth of new blood vessels, a process known as angiogenesis, is necessary for cancerous tumors to grow beyond a certain size. The new blood vessels allow tumors to obtain the oxygen and nutrients needed for continued growth.
Angiogenesis begins when tumor cells or other cells in the microenvironment around a tumor release certain signaling molecules called angiogenesis factors. When these signaling molecules bind to receptors on the surface of nearby endothelial cells, they trigger a series of events that lead to the growth of new blood vessels.
Cancer researchers have been keenly interested in developing ways to block angiogenesis, reasoning that treatments that inhibit this process may prevent tumor growth. Several targeted therapies have already been developed that interfere with the function of a protein called vascular endothelial growth factor (VEGF), which is a key angiogenesis signaling molecule, or with other molecules that respond to VEGF signaling. However, important questions remain about how angiogenesis is regulated. A better understanding of this process could lead to new approaches to blocking angiogenesis in tumors.
In addition to molecular signals such as VEGF, mechanical forces can also affect angiogenesis. These mechanical forces involve, in part, physical interactions between endothelial cells and the supportive fibrous material that surrounds them, which is known as the extracellular matrix (ECM). (Note: Most cells in the body are embedded in ECM; this material provides structural support for cells and performs other important functions.) Researchers wanted to know how these mechanical forces work together with molecular signals to regulate angiogenesis.
Previous studies had shown that shape changes in endothelial cells induced by physical stress affect a protein called p190RhoGAP. In skin cells, this protein interacts with a transcription factor called TFII-I. Transcription factors bind to DNA in the nucleus of cells and turn specific genes on or off. Researchers also knew that TFII-I regulates the expression of VEGFR2 (vascular endothelial growth factor receptor 2), a receptor for VEGF in endothelial cells.
These findings suggested that p190RhoGAP might regulate VEGFR2 expression in endothelial cells through its effects on TFII-I. To examine this possibility, researchers experimentally manipulated the levels of p190RhoGAP, TFII-I, and GATA2—another transcription factor that regulates VEGFR2 expression—in endothelial cells. The results showed that p190RhoGap controls VEGFR2 expression and angiogenesis by altering the balance between TFII-I and GATA2, which have opposing effects: GATA2 stimulates VEGFR2 expression and angiogenesis, whereas TFII-I inhibits them. Experiments involving mouse retinas, in which angiogenesis is tightly regulated, gave similar results, confirming the findings are relevant in living animals.
To study the effects of mechanical interactions between cells and the ECM on this newly discovered regulatory pathway, researchers grew endothelial cells on surfaces with different degrees of stiffness. They also examined the ability of endothelial cells to form capillaries when grown within an artificial ECM implanted below the skin of mice. In both cases, changes in surface stiffness or ECM elasticity (mechanical signals) affected VEGFR2 gene expression and new blood vessel growth through p190RhoGap and the transcription factors TFII-I and GATA2. VEGF and other molecules stimulate angiogenesis through the same signaling pathway.
Taken together, the results reveal a previously unknown angiogenesis signaling pathway that is sensitive to both molecular signals (such as VEGF) and mechanical forces. These results provide insight into how mechanical and molecular signals are integrated to regulate blood vessel formation. Development of drugs that specifically modify this pathway could lead to new treatment approaches for cancer and other angiogenesis-dependent diseases, such as arthritis and certain eye diseases that can lead to blindness.Reference: Mammoto A, Connor KM, Mammoto T, et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature (2009); 457: 1103-1108.
More summaries of selected scientific advances from NCI-supported research are available at http://www.cancer.gov/aboutnci/servingpeople/advances.