Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in growth and development, as well as in wound healing. It plays a significant role in the process of conversion of tumours to a malignant state from a dormant state. It is also a major pathological component of diseases such as cancer and coronary heart disease.

The angiogenesis and its importance as a target in many pathological diseases, including cancer, coronary heart disease and neurological diseases, is a hot area of active research. Understanding of various molecular steps and the cellular processes for the angiogenesis has indicated its potential applications. The vascular endothelial growth factor (VEGF), basic fibroblasts growth factor (BFGF) etc. are currently focused on chemotherapeutic targets, which can be exploited as potential targets for the development of anti angiogenic drugs. The various plant based derivatives and functional foods with angiostatic activity are explored for prevention or reduction of the incidence of angiogenesis in cancer.

In 1994, the Angiogenesis Foundation declared angiogenesis as a 'common denominator' in the most important diseases states, in which the body loses control of angiogenesis. For example, in chronic wound, coronary artery disease, stroke and non-union fracture, inadequate growth of blood vessels (in size and/or number) may lead to poor blood circulation with a risk of tissue death. And in alopecia, hair loss is attributed to insufficient angiogenesis caused by the inadequate production of angiogenesis growth factors and/or excessive amounts of angiogenesis inhibitors. Therapeutically angiogenesis can be directed to stimulating neo vascularization with the help of growth factors, which is being developed to reverse above conditions.

On the contrary, in diseases such as cancer, psoriasis and endometriosis, excessive angiogenesis occur when diseased cells produce abnormally large amounts of angiogenesis factors [e.g. VEGF, fibroblast growth factor (FGF)-2 and hepatocyte growth factor] negating the effects of natural angiogenesis inhibitors (e.g. angiostatin, endostatin and thrombospondin). More than 70 other conditions, including obesity and asthma, are associated with excessive angiogenesis. In these conditions, new blood vessels feed diseased tissues and destroy normal tissues. There are ten sequential steps of angiogenesis involving stimulators and inhibitors of angiogenesis.They are:

#.In response to hypoxia, injured or diseased tissues synthesize and release angiogenic factors

#.Angiogenic factors bind to their receptors on endothelial cells (ECs)

#.Receptor binding leads to EC activation

# Proteases are released to dissolve the basement membrane

#.ECs migrate and proliferate

# Adhesion molecules (e.g. integrin avb3 and avb5) help to pull the sprouting blood vessel forward

# Matrix metalloproteinases (MMPs) are produced to dissolve the extracellular matrix and to initiate remodeling

#.Angiopoietin-Tie-2 interaction modulates tubule formation

#.The EphB-ephrinB system regulates loop formation

#.Pericytes are incorporated to stabilize the newly formed blood vessel

#.As in cancer, tumour cells use the new vessels to escape into the general circulation and lodge in other organs, which may lead to tumour metastases.

The factors involved in angiogenesis include VEGF-A and other angiogenic factors such as bFGF, angiopoietins, interleukin-8, placental-like growth factor (PlGF) and VEGF-C. These angiogenic factors stimulate resident endothelial cells to proliferate and migrate. An additional resource of angiogenic factor is the stroma. Stroma is a heterogeneous compartment, comprising fibroblastic, inflammatory and immune cells.

Recent studies indicate that tumour associated fibroblasts produce chemokines such as stromal cell-derived factor (SDF1), which may recruit bone-marrow-derived angiogenic cells (BMC). VEGF-A or PlGF may also recruit BMC. Tumour cells may also release stromal cell-recruitment factors, like platelet derived growth factor-A (PDGF-A), PDGF-C or transforming growth factor (TGF)- . A well-established function of tumour-associated fibroblasts is the production of growth/survival factor for tumour cells, including EGFR ligands, hepatocyte growth factor and heregulin. The Endothelial cells produce PDGF- , which promotes recruitment of pericytes in the microvasculature after activation of PDGFR-, HGF hepatocyte growth factor.

Brain tumour angiogenesis is another example for the ability of the adult brain to produce new blood vessels. But it presents serious clinical problems as it allows tumours to grow to sizes within the rigid confines of the skull, which can cause brain herniation and death.

Hypoxia or ischaemia can induce angiogenesis in most tissues, including the brain. In adult humans, pure hypoxia is rare, but cerebral ischaemia can be incidental. Transient global ischaemia, which complicates cardiac arrest, causes death of intrinsically susceptible neurons, including those in some of the specified regions of the hippocampus and of cells in selectively vulnerable areas, like the vascular watershed or border zones of the brain and spinal cord.

Most often, vascular brain injury is caused by focal cerebral ischaemia, which may be transient or permanent. It is usually attributed to atherosclerotic occlusion or embolism within an artery. Focal cerebral ischaemia of sufficient severity and duration may result in death of tissue, infarction, produces stroke, which is characterized by a persistent disturbance of neurological function associated with damage to a discrete area of the brain. Some cerebral disorders are associated with hemorrhage, rather than ischaemia.

In addition to tumour cells, the intended target for chemotherapy in cancer patients, conventional chemotherapy drugs can inhibit the proliferation of, or kill, a number of normal host cell types. It can, however, contribute to an antiangiogenic effect. Targeting of various normal cell populations is generally associated with harmful or undesirable side effects such as myelosuppression, alopecia or mucositis.

Bone-marrow-derived pro angiogenic cells that adhere to the walls of new blood vessels can be further stimulated to growth by paracrine mechanisms. Whether these latter cell types, which probably include monocytes and pericytes precursors, are affected directly by chemotherapy or are reduced in numbers by elimination of more primitive bone marrow progenitors, which give rise to such cells, is not yet clearly established. The bone-marrow-derived circulating endothelial progenitor cells (EPC) that can incorporate into the lumen of growing vessels and differentiate into endothelial cells are found inhibiting the levels or function of VEGF can augment these various antiangiogenic mechanisms of chemotherapy. For instance, VEGF is a potent mobilizes of EPC, a prosurvival (anti-apoptotic) factor for differentiated, activated endothelial cells and may be one of the more important paracrine growth factors secreted by pro angiogenic vessel adherent bone-marrow-derived monocytes.

The phytochemicals as a source of angiogenesis-modulating compounds is quite promising. Some plant-derived anticancer drugs are antiangiogenic include taxol, an extract from the bark of the pacific yew tree (Taxus brevifolia)

Taxol kills proliferating cancer cells by disrupting their microtubule cytoskeletons. Of particular interest is the recent discovery that, at low pico molar concentrations, taxol is antiangiogenic, inhibiting VEGF production and hypoxia-inducible factor (HIF)a protein expression. The data support a clinical application of continuous ultra-low-dose taxol to treat cancer. The camptothecin is a crude plant extract from the Chinese tree camptotheca acuminata. Camptothecin traps topoisomerase I in complexes with DNA, thus preventing DNA replication and resulting in the death of the cancer cell. Combretastatin is a microtubule-targeting agent found in the bark of the African bush willow tree (Combretum caffrum).

Antiangiogenic functional foods include soybeans, which is rich in isoflavones. In soya, genistein is the most potent at inhibiting EC proliferation and in vitro angiogenesis. The green tea and one of its components, epigallocatechin-3-gallate (EGCG), significantly prevent angiogenesis. Resveratrol, which is present in red wine, peanuts, mulberries and medicinal plants such as polygonum cuspidatum, inhibits angiogenesis without causing severe side effects when administrated orally.

There are many mechanisms which underlie the process of angiogenesis. Angiogenesis may some times be useful and some times be harmful depending on circumstances. Many classes of therapeutic drug classes are being identified in treating against angiogenesis. However, all these classes suffer from their own severe side effects in the course of therapy. Hence, it is better to control angiogenesis with natural products as it presents fewer side effects than the synthetic ones. Other novel approaches, including working at the gene level to modify the pathogenesis and stem cell approaches must be well developed for treating diseases in which angiogenesis plays an important role.

(Anantha Naik Nagappa and Ramkrishna Prasad are with dept. of Pharmacy Practice, Shirdi Saibaba Cancer Hospital, Manipal & S Dewakar is with Pharmacy Group, Birla Institute of Technology & Science, Pilani, Rajasthan.)