Nicotine-dependent recruitment of vascular progenitor cells
Initial Award Abstract
The effects of tobacco use are very complex. Tobacco smoke contains more than 4000 separate chemical compounds, each of which may have its own individual effect as well as effects that are interactive with those of other components. Nicotine provides a good example of this complexity. Well known for its powerful addictive properties, nicotine is also a potent inducer of new blood vessel formation. Significantly, the growth of new blood vessels is a key element of several types of diseases that are linked to tobacco use. For example, cancerous tumors are caused by carcinogens present in tobacco. Once initiated by carcinogens, the tumors require an increasing blood supply to satisfy their nutritional demands. Tumors use many tricks to attract new blood vessels, but the action of nicotine makes their job easier by jump-starting blood vessel growth. Another example is stress on the lungs and airways caused by tobacco-derived agents. This leads to thickening and narrowing of blood vessel walls due to overgrowth of cells that line the vessels. Like tumors, once they are initiated, these growing cell masses require an increasing blood supply to maintain their needs. Nicotine helps to meet this need. In both of these examples, nicotine has a double role. It not only accelerates the disease process by stimulating blood vessel formation, but also reinforces continued tobacco use by virtue of its addictive properties. This combination all but guarantees the eventual success of the disease.
The ability to deal effectively with the actions of nicotine requires an understanding of the mechanisms by which the molecule works. Treatment of addiction requires a knowledge of how the drug affects the function of nerve cells in the brain. Coping with increased blood vessel growth requires a knowledge of how cells are stimulated to form blood vessels. This proposal will deal with the second topic, namely the way that nicotine stimulates cells to form new blood vessels. The hope is that by understanding which cells are involved in this process and how they are affected by nicotine, we will find ways of controlling the process to our advantage.
Early results using an experimental model in mice show that nicotine triggers the formation of new blood vessels by activating a specific type of stem cell. These cells have their origin in the bone marrow, which is a rich source of stem cells. An increasing number of studies are now revealing an important role for bone marrow stem cells in the formation of new blood vessels in various types of diseases. Nicotine seems to stimulate the participation of a very specific type of stem cells that we can recognize by virtue of molecules present on their surface. At the site of new blood vessel growth, these cells first form a primitive blood vessel-like structure and then give rise to the two different cell types that are required to form the inner and outer linings of mature blood vessels. The work proposed in this application will lead to a better understanding of this process through the following specific aims.
(1) The development of stem cells into two distinct types of blood vessel cells will be studied in a mouse model of nicotine-induced blood vessel formation. Developmental changes in individual cells will be followed by microscopy techniques that also allow evaluation of the function of the blood vessel as a whole.
(2) The ability of nicotine to attract a specific population of bone marrow stem cells will be studied using mice in which the bone marrow cells are marked with a fluorescent tag. This allows us to follow these cells and determine not only which cells are initially affected by nicotine, but also where they end up in the blood vessels.
(3) Cell culture experiments will be performed with the bone marrow stem cells to determine how they are affected by nicotine. We want to know if nicotine activates these cells by increasing their ability to proliferate, migrate, or change their shape. These studies of mechanisms may yield clues about ways to control the action of nicotine. |
|FGF2-dependent neovascularization of subcutaneous Matrigel plugs is initiated by bone marrow-derived pericytes and macrophages.
|Authors: Tigges, U., Hyer E.G., Stallcup, W.B.