Angiogenesis Cut Dis

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Text of Angiogenesis Cut Dis

Angiogenesis and its role in cutaneous diseasesModerator : Prof. A. J. Kanwar

Introduction

Angiogenesis is the growth of new blood vessels from preexisting ones It is a normal process in

Growth development female reproductive cycle and wound healing

However, it is also a key element in disease pathogenesis

Process of angiogenesis in disease

Angiogenesis is controlled in a healthy body by a system of angiogenic growth factors and angiogenesis inhibitors

It is induced when there is an imbalance of angiogenic growth factors compared to angiogenesis inhibitors - the angiogenic switch

The phosphatidylinositol 3-kinase(PI3K)/ Akt/ mammalian Akt/ target of rapamycin (mTOR) pathway plays an important role mTOR) in angiogenesis

Steps in angiogenesis

Diseased or injured tissues up-regulate the expression of upangiogenic growth factors and release these products to adjacent tissues Growth factors bind to specific receptors located on nearby endothelial cells, resulting in cell activation Signals are sent from the cells surface to the nucleus Endothelial cells then begin to proliferate and secrete proteases (MMPs) to migrate towards the injured/diseased tissues to degrade the existing vessels basement membranes

Steps in angiogenesis

As tracks are formed, endothelial cells differentiate, divide, and migrate

Remodeling occurs in tissues adjacent to the vessels

Endothelial cells eventually anastomose into hollow tubes produce a new basement membrane and secrete growth factors to attract supporting cells like periyctes, periyctes, which stabilize the new vessels

Angiogenic growth factorsVascular endothelial growth factor (VEGF) Believed to be the most potent and predominant angiogenesis stimulator and it appears to play a key role in angiogenesis related cutaneous disease

Many of the angiogenesis inhibitors that are approved by the USFDA are aimed at neutralizing VEGF or its receptors Members of VEGF family stimulate cellular responses by binding to VEGF receptors (VEGFRs) on cell surfaces

Vascular endothelial growth factor (VEGF)

VEGF binds to two known receptors, t-1(VEGFR1) and kdr t(VEGFR2), which are tyrosine kinase receptors (RTKs)

The angiogenic effects of VEGF are mediated primarily through VEGFR2 The primary target of VEGF is the endothelial cell and effects are mediated through multiple pathways

Vascular endothelial growth factor (VEGF)

VEGF has many activities and functions, including:

increasing endothelial cell migration, endothelial cell mitoses and vascular permeability promoting chemotaxis for granulocytes and macrophages indirectly promoting vasodilatation via nitric oxide release

VEGF has also been shown to regulate blood vessel diameters when binding to VEGFR2 Low concentrations of VEGF promote long and thin vessels, while higher concentrations result in increased vessel diameters

Angiopoietin

There are actually four angiopoietins (Ang1, Ang2, Ang3 and Ang4), but Ang1 and Ang2 are the best characterized Ang1 is expressed in pericytes, smooth muscle cells, pericytes, fibroblasts and some tumor cells By contrast, Ang2 is almost exclusively expressed by endothelial cells and is also detectable in Kaposi sarcoma (KS) cells Both Ang1 and Ang2 bind to the RTK Tie2, which is expressed on the surface of endothelial cells

Angiopoietin

Binding of Ang1 to Tie2 activates the receptor through autophosphorylation and promotes endothelial cell migration and survival Unlike VEGF, Ang1 does not directly induce endothelial cell proliferation By contrast, Ang2 binding to Tie2 does not activate the receptor and it may function as an antagonist to Ang1 Interestingly, in the absence of VEGF, Ang2 contributes to vascular regression; but in its presence, may stimulate angiogenesis

Basic fibroblast growth factor ( FGF) FGF)

FGF was one of the rst angiogenic factors to be isolated FGF acts as an endothelial cell mitogen, inducing tube mitogen, formation and protease production It also acts as a mitogen for keratinocytes and may stimulate epithelialization FGF has been noted to increase both epithelialization and capillary infiltration in dermal wound healing Melanoma cells are well known to secrete FGF and inhibition of FGF synthesis inhibits tumor growth

Interleukin-8(ILInterleukin-8(IL-8)

Is a proinammatory chemokine found in monocytes, monocytes, macrophages and other nonimmune cells

ILIL-8 binds with high affinity to two receptors, CXCR1 and CXCR2

Binds to G protein coupled receptors, activating the downstream pathway of PI3K/Akt and MAPK to control cell PI3K/Akt survival, angiogenesis and migration

PlateletPlatelet-derived growth factor (PDGF)

PDGF up-regulates VEGF mRNA expression and this may be upthe mechanism for its involvement in vascular diseases PDGF has also been shown to promote dermal wound healing and it is required by pericytes, which stabilize normal and pericytes, tumor vasculature PDGF and its receptors have also been strongly linked to fibrotic diseases, including scleroderma, where expression was mainly concentrated around blood vessels Receptors for PDGF are expressed in KS spindle cells and have been associated with KS, both in the induction of spindle cell growth and angiogenesis

Transforming growth factor -

TGF normally acts as a tumor suppressor but can promote tumor angiogenesis when aberrantly expressed

TGF may promote tumor angiogenesis by inducing the expression of IL-8 and VEGF IL-

Tumor necrosis factor -

TNF activates B cells and the MAPK pathway to induce upregulation of other angiogenic factors, including IL-8, ILVEGF and MMPs

Angiogenesis inhibitors

Angiostatin Its antiangiogenic effects result from

apoptosis of the vascular endothelial cells and resultant tumor regression inhibition of both bFGF and VEGF endothelial cell mitotic arrest cessation of plasmin formation (plasmin partakes in tumor invasion) (plasmin binding to subunits of ATP synthase on the outer membranes of endothelial cells

Endostatin

Endostatin is a fragment from collagen XVIII that functions as an endogenous inhibitor of endothelial proliferation and angiogenesis It acts by competitively binding to VEGFR2 Endostatin also blocks effects of FGF and various MMPs

Interferons

and

Interferons and are thought to inhibit angiogenesis by downdown-regulating IL-8, FGF and MMP-9 ILMMPThese drugs have been used to treat a wide range of diseases, including KS and hemangiomas, where the antiangiogenic hemangiomas, properties are likely to play a role

InterleukinInterleukin-12 and interferonILIL-12s antiangiogenic action is carried out by induction of IFN , MMPs and interferon-inducible protein10 (IP-10) interferon(IPILIL-12 induced IFN leads to decreased endothelial cell adhesion and survival and decreased production of VEGF in malignant cells

ThrombospondinThrombospondin-1

TSPTSP-1 inhibits the migration of endothelial cells and induces apoptosis by binding to the endothelial cell membrane It also binds to and activates TGF - , which leads to tumor growth inhibition TSPTSP-1inhibits the activity of multiple angiogenic factors, including VEGF, FGF, IL-8 and MMP-9 FGF, ILMMP-

Tissue inhibitors of matrix metalloproteinases (TIMPs)

Have the critical role of counterbalancing the activity of MMPs, to prevent the uncontrolled destruction of tissue

The role of TIMPs in angiogenesis is complex, involves both stimulatory and inhibitory effects

TIMPTIMP-2 inhibits the proliferation of FGF-stimulated endothelial cells FGFTIMPTIMP-3 binds to VEGFR2 and interferes with receptor activation and TIMPTIMP-4 has both pro and antiangiogenic activity

Additional elements central to angiogenesis

The PI3K/Akt signaling pathway is central to the regulation of PI3K/Akt angiogenesis and other cellular processes

Many angiogenic growth factors phosphorylate PI3K resulting in the activation of Akt, which leads to inhibition of Akt, endothelial cell apoptosis

Mammalian target of rapamycin

mTOR is a downstream mediator of PI3K/Akt pathway PI3K/Akt This kinase plays a central role in angiogenesis, cell growth and cell cycle progression Agents that target mTOR inhibit signals required for angiogenesis, cell cycle progression, cell growth and proliferation in normal and malignant cells

HypoxiaHypoxia-inducible factor

During tumor development, proliferating cells have increased requirements for oxygen and nutrients In order to proliferate, tumors often respond to this hypoxic stress by stimulating cellular metabolism and neovascularization An important regulator of cellular response to oxygen deprivation is the transcription factor HIF-1 HIFUnder regular oxygen conditions, HIF-1 is continuously HIFexpressed but rapidly destroyed

HypoxiaHypoxia-inducible factor

Low oxygen tension results in a decrease in the rate of HIF -1 proteolysis and its subsequent accumulation HIF1 is a constitutively expressed nuclear protein The resulting (HIF-1 - HIF-1 ) heterodimers undergo (HIFHIFposttranslational modifications and promote angiogenesis, tumor growth and metastasis

Role of angiogenesis in specic cutaneous diseases

Psoriasis

Psoriatic lesions are highly angiogenic showing

increased endothelial cell proliferation dilation of capillary beds tortuosity of capillary loops augmented blood ow through skin and increased capillary permeability

Although some cytokines implicated in psoriasis such as IL-12 ILhave anti-angiogenic effects, the net overall effect of the anticytokine milieu (by IL-8, IL-15, IL-17, IL-20, IL-23 and IL- ILIL- IL