The CO2 level as a factor stimulating angiogenesis Phenomena of tissue regeneration and destruction

The regeneration of vessels and their development occur in places of their destruction. This phenomenon suggests that the destruction process itself stimulates vascular development and entails tissue healing and self-repair. Understanding the phenomena of self-repair is extremely important in the process of restoring tissues and organs to the proper functioning of individual organs and the entire body. Therefore, the recognition of angiogenesis processes seems to be the key in the treatment of many diseases.

Views on the role of endothelium in angiogenesis are widely published [1, 2, 7, and 10]. Various substances have been proposed as a factor in the development of arteries, including vitamin D3. An important role in the development of angiogenesis is also attributed to perisytes, i.e. unorganized stem cells present in the vicinity of blood vessels [4]. The literature in many publications also reports on the formation of new vessels in neoplastic tissues [14. 32, 34, 36, 39]. The literature also provides examples of phenomena that inhibit the development of angiogenesis [3], often based on their computer modeling [5,11].
Literature information and the results of own research suggest a similar cause of angiogenesis in various cases of vascular formation. This view will be presented below.

Collateral circulation
In vessels blocked by substances crystallizing in them [18,26], e.g. coronary vessels, the level of CO2 increases. This is the result of hypoxia, i.e. a change in the ratio between the oxygen level and the CO2 level at the point of blockage. Therefore, in the area of the artery blockage the oxygen level is low compared to the CO2 level, which increases as a result of the death of myocardial cells. Consequently, this phenomenon leads to the formation of easily dissociating carbonic acid (H2CO3), formed from the local CO2 and water present in the tissues. As a result of this, the pH of the environment drops below 7.0. The angiogenesis itself, developing at the site of arterial blockage, can lead to the formation of collateral circulation (Photo 1). Photo 1. Development of secondary vessels (arrows) near a blocked coronary artery. Magnification 150x.

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Auctores Publishing -Volume 1(2)-008 www.auctoresonline.org Page 2 of 5 In the case of neoplastic tumors, the newly formed concentrations of cells form numerous blood vessels that develop from both primary and secondary vessels (Photo 2). The rate at which these blood vessels form is often slower than the rate at which new cells are formed. That results in an increase in non-discharged CO2 causing local acidification of the environment.

Photo 2.
Numerous secondary blood vessels in the Liczne, wtórne naczynia krwionośne in a tumor of the lower base of thigh [32].
The phenomena described in this publication and their interpretation are based on studies of damaged arterial walls. It was noted that a damaged (for various reasons) artery wall may heal itself. The endothelial surface, which proliferates as a result of angiogenesis, forms particular structures that in further evolution lead to the formation of a new artery (Photo 3).

Photo 3.
Endothelial growth phase at the site of damaged artery wall. Arrows show endothelial proliferation of the damaged artery. Scanning microscope, magnification according to scale.

The phenomenon in the cell membrane of intima
Endothelium is the site of many biochemical phenomena. One of the most important is the synthesis of prostacyclins, prostaglandins and thromboxanes, which are secreted into the blood and regulate its properties, including coagulability and the ability to aggregate. Research shows that individual elements of the cell membrane of intima have different functions (Figure 1).

Figure 1.
A general structure of a fragment of the intima cell membrane [38] Angiogenesis in a blocked artery (e.g. coronary vessel) Concentrations of cholesterol crystallizing in and on the artery wall can inhibit blood flow. This causes local increase in CO2 content in relation to the content of oxygen, which is not supplied by the blocked artery. The phenomenon causes local CO2 to react with water, leading to the formation of carbonic acid (H2CO3). It dissociates easily and breaks down into free protons (H + ) and CO3 2carbonate groups. The above phenomena lead to a decrease in the local pH and development of acidic environment that is aggressive towards the artery, where the flowing blood has a pH of 7.2-7.3. The result is that the acidic environment damages the endothelium of the artery.  Protons and carbon from the CO3 2groups build new biological structures at the site of damage to the endothelial cell membrane (blue arrows). The newly formed vessel (artery) proliferates in the direction shown by the yellow arrows.

Angiogenesis in cancerous tumors
In the case of angiogenesis in cancerous tumors, the phenomenon is similar. However, the cause of the local increase in the level of CO2 is different than in the case of artery blockage. Here, the reason is the huge number of cells that multiply, each of them producing carbon dioxide in its life processes. The locally existing blood vessels are not able to evacuate the excess, which results in an increase in its quantity. The next stages of the phenomenon of angiogenesis generation and development proceed as described above, in the case of arterial blockage (Figure 3). Damaged endothelium proliferates using "local material" in the form of protons and carbon to rebuild and initiate a new vessel.

Angiogenesis in a broken bone
While the cause of angiogenesis in bone fracture healing is different, it actually comes down to the phenomena described above for blocked arteries and tumors. In this case, there is also a local increase in the CO2 level. It is caused by the rupture of blood vessels during the fracture. The environment at the fracture site (especially in the fracture gap) contains an increased amount of CO2. This is caused by the inability to drain it through damaged vessels. Increased amount of carbon dioxide leads to the formation of dissociating carbonic acid and the phenomenon continues as described for blocked arteries and tumors.
Due to the fracture, the arteries are damaged mainly in the form of ruptures. Thus, the damage occurs at the tips of the broken arteries, and that is where angiogenesis begins. As a result, the proliferation of newly formed vessels in the fracture zone takes place from the bone fracture to the bone fracture ( Figure 4). The process of angiogenesis itself is similar to that in tumors and blocked vessels. The phenomenon of new artery generation in the artery endothelium at the site of vessel rupture. Material for the newly developing artery is collected from the local environment (blue arrows). The direction of growth of the newly formed vessel runs roughly from one bone fragment to the other (yellow arrows).

Conclusion:
1. Angiogenesis develops in areas with arterial damage, i.e. places where excess CO2 cannot be discharged through damaged vessels (veins). Another area with excess CO2 are cancer tissues, where the levels of CO2 raise due to fast increase in number (proliferation) of cells.
2. Locally high level of CO2 leads to the formation of aggressive carbonic acid H2CO3, which can destroy the cell membrane of endothelial cells.
3. Damaged areas are places where the atomic structures of the organic components that make up the intima cell membrane have a broken interatomic bond. 4. These damaged areas in the structure of endothelial cell membranes are endowed with electric charges. This is where the formation of new vessels (angiogenesis) starts. 5. The "building blocks" for the development of new vessels are hydrogen and calcium from easily-dissociated H2CO3 that is created from the excess CO2.
6. Depending on the cause of the arterial damage, angiogenesis develops along the axis of the vessel (in fractures) or in multiple directions (collateral circulation of blocked arteries or neoplastic tissue). 7. Considering the above observations, it is possible to accelerate or inhibit the development of angiogenesis by regulating the local level of CO2.
8. If it is necessary to accelerate angiogenesis, the CO2 level in the area of the blocked artery or bone fracture should be locally increased. 9. If it is necessary to stop angiogenesis, the locally produced carbonic acid needs to be neutralized. This is important in blocking tumor angiogenesis and thus fighting the disease. 10. Separate studies are required to fully identify methods of accelerating and blocking angiogenesis.