Angiogenesis
Angiogenesis | |
---|---|
Identifiers | |
MeSH | D000096482 |
Anatomical terminology |
Angiogenesis is the physiological process through which new
Angiogenesis is a normal and vital process in growth and development, as well as in
Types
Sprouting angiogenesis
Sprouting angiogenesis was the first identified form of angiogenesis and because of this, it is much more understood than intussusceptive angiogenesis. It occurs in several well-characterized stages. The initial signal comes from tissue areas that are devoid of vasculature. The
As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in
Intussusceptive angiogenesis
Intussusceptive angiogenesis, also known as splitting angiogenesis, is the formation of a new blood vessel by splitting an existing blood vessel into two.
Intussusception was first observed in
Coalescent angiogenesis
Coalescent angiogenesis is a mode of angiogenesis, considered to be the opposite of intussusceptive angiogenesis, where capillaries fuse, or coalesce, to make a larger bloodvessel, thereby increasing blood flow and circulation.[12] Coalescent angiogenesis has extended out of the domain of embryology. It is assumed to play a role in the formation of neovasculature, such as in a tumor.[13]
Physiology
Mechanical stimulation
Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to shear stress acting on capillaries to cause angiogenesis, although current knowledge suggests that increased muscle contractions may increase angiogenesis.[14] This may be due to an increase in the production of nitric oxide during exercise. Nitric oxide results in vasodilation of blood vessels.
Chemical stimulation
Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g. integrins and prostaglandins, including several growth factors e.g. VEGF, FGF.
Overview
Stimulator | Mechanism |
---|---|
FGF | Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts |
VEGF | Affects permeability |
NRP-1 |
Integrate survival signals |
Ang2 |
Stabilize vessels |
PDGFR |
recruit smooth muscle cells
|
TGF-β receptors |
↑extracellular matrix production |
CCL2 | Recruits lymphocytes to sites of inflammation |
Histamine | |
Integrins αVβ3, αVβ5 (?[15]) and α5β1 | Bind proteinases
|
VE-cadherin and CD31 | endothelial junctional molecules
|
ephrin | Determine formation of arteries or veins |
plasminogen activators | remodels extracellular matrix, releases and activates growth factors |
plasminogen activator inhibitor-1 | stabilizes nearby vessels |
COX-2 |
|
AC133 | regulates angioblast differentiation |
ID1/ID3 | Regulates endothelial transdifferentiation |
Class 3 semaphorins | Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability[16] |
Nogo-A | Regulates endothelial cell migration and proliferation.[17] Alters vascular permeability.[18] |
FGF
The
Besides FGF-1, one of the most important functions of fibroblast growth factor-2 (FGF-2 or
VEGF
Angiopoietins
The
MMP
Another major contributor to angiogenesis is
Dll4
Class 3 semaphorins
Chemical inhibition
An angiogenesis inhibitor can be endogenous or come from outside as drug or a dietary component.
Application in medicine
Angiogenesis as a therapeutic target
Angiogenesis may be a target for combating diseases such as
The modern clinical application of the principle of angiogenesis can be divided into two main areas: anti-angiogenic therapies, which angiogenic research began with, and pro-angiogenic therapies. Whereas anti-angiogenic therapies are being employed to fight cancer and malignancies,
Regarding the
There are still serious, unsolved problems related to gene therapy. Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity,
By contrast, pro-angiogenic protein therapy uses well-defined, precisely structured proteins, with previously defined optimal doses of the individual protein for disease states, and with well-known biological effects.[1] On the other hand, an obstacle of protein therapy is the mode of delivery. Oral, intravenous, intra-arterial, or intramuscular routes of protein administration are not always as effective, as the therapeutic protein may be metabolized or cleared before it can enter the target tissue. Cell-based pro-angiogenic therapies are still early stages of research, with many open questions regarding best cell types and dosages to use.
Tumor angiogenesis
Cancer cells are cells that have lost their ability to divide in a controlled fashion. A
Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g.
Endothelial cells have long been considered genetically more stable than cancer cells. This genomic stability confers an advantage to targeting endothelial cells using antiangiogenic therapy, compared to
Formation of tumor blood vessels
The mechanism of blood vessel formation by angiogenesis is initiated by the spontaneous dividing of tumor cells due to a mutation. Angiogenic stimulators are then released by the tumor cells. These then travel to already established, nearby blood vessels and activates their endothelial cell receptors. This induces a release of
Angiogenesis for cardiovascular disease
Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely neoangiogenesis: the production of new collateral vessels to overcome the ischemic insult.[21] A large number of preclinical studies have been performed with protein-, gene- and cell-based therapies in animal models of cardiac ischemia, as well as models of peripheral artery disease. Reproducible and credible successes in these early animal studies led to high enthusiasm that this new therapeutic approach could be rapidly translated to a clinical benefit for millions of patients in the Western world with these disorders. A decade of clinical testing both gene- and protein-based therapies designed to stimulate angiogenesis in underperfused tissues and organs, however, has led from one disappointment to another. Although all of these preclinical readouts, which offered great promise for the transition of angiogenesis therapy from animals to humans, were in one fashion or another, incorporated into early stage clinical trials, the FDA has, to date (2007), insisted that the primary endpoint for approval of an angiogenic agent must be an improvement in exercise performance of treated patients.[49]
These failures suggested that either these are the wrong molecular targets to induce neovascularization, that they can only be effectively used if formulated and administered correctly, or that their presentation in the context of the overall cellular microenvironment may play a vital role in their utility. It may be necessary to present these proteins in a way that mimics natural signaling events, including the concentration, spatial and temporal profiles, and their simultaneous or sequential presentation with other appropriate factors.[50]
Exercise
Angiogenesis is generally associated with
Macular degeneration
Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of vision. Anti-angiogenic drugs targeting the VEGF pathways are now used successfully to treat this type of macular degeneration
Tissue engineered constructs
Angiogenesis of vessels from the host body into an implanted tissue engineered constructs is essential. Successful integration is often dependent on thorough vascularisation of the construct as it provides oxygen and nutrients and prevents necrosis in the central areas of the implant.[51] PDGF has been shown to stabilize vascularisation in collagen-glycosaminoglycan scaffolds.[52]
History
The first report of angiogenesis can be traced back to the book A treatise on the blood, inflammation, and gun-shot wounds published in 1794, where Scottish anatomist John Hunter's research findings were compiled. In his study, Hunter observed the growth process of new blood vessels in rabbits. However, he did not coin the term "Angiogenesis," which is now widely used by scholars. Hunter also erroneously attributed the growth process of new blood vessels to the effect of an innate vital principle within the blood. The term "angiogenesis" is believed to have emerged not until the 1900s. The inception of modern angiogenesis research is marked by Judah Folkman's report on the pivotal role of angiogenesis in tumor growth.[8][53][54]
Quantification
Quantifying vasculature parameters such as microvascular density has various complications due to preferential staining or limited representation of tissues by histological sections. Recent research has shown complete 3D reconstruction of tumor vascular structure and quantification of vessel structures in whole tumors in animal models.[55]
See also
References
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