18-23_newton's Law In Angiogenesis

Angiogenesis and Newton′s law

Newton′s law in angiogenesis

Nourozpour A, Mehdizadeh AR, Fazelzadeh A Sadra–Sina Interdisciplinary Research Group Mashad University of Medical Sciences

Abstract Angiogenesis begins with protrusion of capillary wall and formation of new sprouts from pre-existing blood vessels. Broadly accepted today, this process is initiated by releasing some growth factors from a demand area to act on endothelial cells of pre-existing vessels and make them activated and migrated through growth factor gradient. By this viewpoint, many investigations have been done but the real cause of it has not been clearly understood. By reviewing this process, we could look at it through a different point. We hypothesize that mechanical forces act on capillary wall from inside and outside of vessel, may be initiating factor of angiogenesis.

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By considering these forces and controlling them, we could more efficiently handle this process in pathologic conditions. Keywords: Angiogenesis, growth factors, sprout, Newton's law, mechanical force.

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Introduction Angiogenesis refers to sprouting of new vessels from preexisting blood vessels (1). Some investigations demonstrate that this process must be involved in some pathologic conditions, summarized in table 1.To stimulate angiogenesis, some intra and extra vascular factors may affect on endothelial cells (EC). Most of the investigations analyze this process by regarding that some signals, in the form of growth factors, from out of vessels act on ECs to activate them and make them digest their extracellular matrix (ECM) by some enzymes, especially matrix metalloproteinase (MMP), and migrate toward higher concentration of growth factors, Figure 1. In order to stimulate it, some investigations have been done by increasing concentration of growth factors in target tissue. Also, to inhibit it, some growth factors or MMPs have been targeted to be blocked. To control this process, we should look at it again and consider all factors that may influence on sprout formation. How a new sprout forms? At the beginning of angiogenesis, in order to new sprout formation, capillary wall must be protruded outward. In most of investigations, it has been proposed that the cause of this protrusion is some growth factors that act on ECs. Then ECs get activated and digest its basement membrane by some enzymes and then, protrude, figure 1. By considering intra and extra vascular factors together, we can conclude that angiogenesis occurs when the balance between intra and extra vascular factors

Table 1. Some pathologic conditions in which angiogenesis may be involved

Conditions in which angiogenesis must get stimulated. Myocardial ischemia2 Peripheral ischemia1 Wound healing1 Conditions in which angiogenesis must get inhibited. Tumor growth3 Diabetic retinopathy4,5 Retinopathy of prematurity5 Rheumatoid arthritis6 Atherosclerotic plaques7 get disturbed. It means that if these factors are in balance, capillary wall would not get protruded but if intravascular factors stimulate capillary wall to be protruded and extra vascular factors facilitate its protrusion, capillary wall get ready to form a new sprout. It is reminiscent of Newton’s first law, as discussed below. Newton's laws of motion: Newton's laws of motion are three physical laws which provide relationships between the forces acting on a body and the motion of the body, first compiled by Sir Isaac Newton. Newton's laws were first published together in his work Philosophiae Naturalis Principia Mathematica (1687). The laws form the basis for classical mechanics. Newton used them to explain many results concerning the motion of physical objects (8).

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Angiogenesis and Newton′s law

Figure 1. Intra and extra vascular forces act on vascular wall

Newtonian’s first law stated as: “Every body perseveres in its state of being at rest or of moving uniformly straight forward, except insofar as it is compelled to change its state by force impressed.” (8). This law is also called the law of inertia. Newton arranged his laws in hierarchical order for good reason (for more details, see reference 9). The net force on an object is the vector sum of all the forces acting on the object. Newton's first law says that if this sum is zero, the state of motion of the object does not change. Essentially, it makes the following point: an object that is not moving will not move until a net force acts upon it. The law serves to emphasize the elementary causes of changes in an object's state of motion: forces.

Hypothesis In our model, intravascular factors include forces which push capillary wall

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outward and extra vascular factors include forces that act on opposite direction of intravascular forces. The intravascular forces are caused by blood pressure within capillary lumen and the extra vascular forces are caused by basement membrane and ECM components and cells that are around capillary wall. Thus, when forces are in balance, capillary wall does not move but if forces from inside increase and forces from outside decrease, capillary wall protrudes, Figure 1.

Discussion Most of investigations analyze angiogenesis process by regarding that some signals, in the form of growth factors, from out of vessels act on ECs to activate them and make them digest their extracellular matrix (ECM) by some enzymes, especially matrix metalloproteinase (MMP), and migrate toward higher concentration of growth factors. It is proposed that a balance

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between pro-angiogenic and antiangiogenic factors control angiogenesis. Thus it is controlled through a series of “on” and “off” regulatory switches: the main “on switches” are known as proangiogenic growth factors; the main “off switches” are known as antiangiogenic factors. When proangiogenic growth factors are produced in excess of anti-angiogenic factors, the balance favors new sprout formation. When inhibitors are present in excess of stimulators, angiogenesis is stopped (1). To interfere therapeutically with this process and control it, too many attempts have been done to identify some pro-angiogenic and antiangiogenic factors, listed in table 2. Thus, to inhibit angiogenesis, some growth factors or MMPs have been targeted to be blocked and to stimulate this process, some of these growth factors have been administered to act on ECs and also some clinical trials have been made to exploit some growth factors therapeutically, especially vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) (2,4,10) but some of them have been disappointing, probably owing to unresolved questions regarding optimal dose, optimal timing, treatment strategies such as protein delivery or its gene delivery (11) and type of growth factor and combinations of them and route of delivery, long-term safety (2,10,12,13,14) Recently, stem cell therapy especially bone-marrow derived stem cells, to stimulate angiogenesis in some diseases like ischemic heart disease (IHD) has been done (15), but those previous questions remained to be solved for growth factor therapy, also remain for this method of treatment. It seems that it might be needed to be reconsidered.

As shown in figure 1, angiogenesis is initiated by protruding capillary wall outward and forming a new sprout. Thus, intravascular forces must be in excess of extra vascular forces. When capillary blood pressure increases, forces act on capillary wall from inside increase. Increasing capillary blood pressure may be caused by local vasodilation in some situations in which demand of a part of the body gets more than its blood supply, like tissue ischemia and tumor growth. As mentioned above forces from outside are caused by supporting structures of capillary wall. Thus, if these supporting structures get destroyed or get away from capillary wall, these forces decrease. For example, in retina, neurons and glial cells act as supporting structures for retinal blood vessels. As a complication of diabetes mellitus, neurons may be destroyed (5). Thus supporting structures of vessels in retina get destroyed. Then, imbalance among forces, act on capillary wall from outside and inside, causes wall to be protruded. Thus micro aneurysms and then, new sprouts form. It is clear that if difference between forces act from inside and outside gets very high and then, net forces that protrude capillary wall gets more than maximal wall tension which it can tolerate, capillary wall ruptures and bleeding occurs.

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Angiogenesis and Newton′s law

Table 2. Some pro–angiogecin and anti–angiogenic factors.

Pro-angiogenic

Anti-angiogenic

VEGF Angiopoietin-1 β-Estradiol FGF IL-8 Leptin MCP-1 MMPs NOS PDGF-BB TNF-α Angiogenin TGF

Angiostatin Anti-angiogenic anti-thrombin III Canstatin Endostatin (collagen XIII fragment) Fibronectin fragment Heparinases IFN-α,β,χ IL4, IL12, IL18 Plasminogen activator inhibitor PEDF Prolactin 16 kDa fragment TSP-1 Retinoids

(Abbreviations: VEGF—vascular endothelial growth factor; FGF—fibroblast growth factor; IL8— interleukin 8; MCP-1—macrophage chemoattractant protein; MMPs—matrix metalloproteases; NOS—nitric oxide synthase; PDGF-BB—platelet derived growth factor-BB; TGF—transforming growth factor; TNF—tumor necrosis factor; IFN-α,β,χ—interferon-α,β,χ; PEDF—pigment epithelium derived growth factor; TSP-1—thrombospondin-1).

Conclusion Thus, by controlling physical forces apply on capillary wall, we can stimulate new sprout formation or inhibit it. In order to stimulate new sprout formation, these physical forces must be high enough to protrude capillary wall and low enough to prevent from its rupture and to inhibit new sprout formation, physical forces from outside must be high enough to prevent capillary wall protrusion.

Acknowledgment We gratefully acknowledge Mahmood Shabestari.

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Dr.

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