Angiogenic Disorders

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After birth, angiogenesis still contributes to organ growth, but during adulthood most blood vessels remain quiescent; angiogenesis only occurs in the cycling ovary and placenta during pregnancy. However, endothelial cells (ECs) retain the remarkable ability of dividing rapidly in response to a physiological stimulus, such as hypoxia and inflammation. Angiogenesis is also reactivated during wound healing and repair. In many disorders, however, this stimulus becomes excessive, and the balance between stimulators and inhibitors is disturbed, resulting in an angiogenic switch. The best-known conditions in which angiogenesis is switched on are malignant, ocular and inflammatory disorders, but many additional processes are affected-such as atherosclerosis, asthma, diabetes, cirrhosis, multiple sclerosis, endometriosis, acquired immunodeficiency syndrome (AIDS), bacterial infections and autoimmune diseases (Table 1). In obesity, adipose tissue may also show excessive growth. A high-fat diet induces an angiogenic gene programme in fat (Li et al. 2002) and angiogenic factors stimulate adipogenesis, while treatment of obese mice with anti-angiogenic agents results in weight reduction and adipose tissue loss (Rupnick et al. 2002). Viral and bacterial pathogens carry angiogenic genes of their own (Meyer et al. 1999), or induce the expression of angiogenic genes in the host (Harada et al. 2000). The human herpesvirus-8 transforms ECs and causes Kaposi's sarcoma in human immunodeficiency virus (HIV)-1-infected AIDS patients (Barillari and Ensoli 2002).

In other diseases, such as ischaemic heart disease or pre-eclampsia, the angiogenic switch is insufficient, thereby causing EC dysfunction, vessel malformation and regression, or preventing revascularisation, healing and regeneration (Table 2). In the skin, age-dependent reductions in vessel density and maturation cause vessel fragility, leading to hair loss and the development of purpura, telangiectasia, angioma and venous lake formation (Chang et al. 2002). A progressive loss of the microvasculature in elderly people has been implicated in nephropathy (Kang et al. 2001), bone loss (Martinez et al.

2002) and impaired re-endothelialisation after arterial injury (Gennaro et al.

2003). Diabetes, atherosclerosis and hyperlipidaemia also impair vessel growth

Table 1 Diseases characterised or caused by abnormal or excessive angiogenesis

Organ

Disease in mice or humans

Numerous Cancer (activation of oncogenes; loss of tumour suppressors)

organs and metastasis; infectious diseases (pathogens that express angiogenic genes (Meyer et al-1999), induce angiogenic programmes

(Harada et al. 2000) or transform ECs (Barillari and Enzoli 2002; Wang et al. 2004)).

vasculitis and angiogenesis in auto-immune diseases such as systemic sclerosis, multiple sclerosis and Sjogren's syndrome

(Kirk and Karlik 2003; Ohno et al. 2004; Storkebaum et al. 2004)

Vasculature Vascular malformations (Tie-2 mutation (Vlkkula et al.1996))

DiGeorge syndrome (low VEGF/Nrp-1 expression, (St*lmans et al 2°°3)); hereditary haemorrhagic telangiectasia (mutation of endoglin or ALK

(van den Driesche et aL 2003; Lebrm et al. mos^ cavernous haemangioma

(loss of Cx37/40 (Simon and McWhorter 2002)); cutaneous haemangioma (VG5Q mutation (Lambrechts and Carmeliet 2004; Tian et al. 2004))

transplant arteriopathy and atherosclerosis

(Kahlon et al. 1992; Khurano et al. 2005; Nakano et al. 2005)

Skin Psoriasis (high VEGF and Tie2

(Xia et al. 2003; Leong et al. 2005; Voskas et al. 2005))

warts (Harada et al.2000); allergic dermatitis (high VEGF and PlGF

(Oura et al. 2003; Agha-Majzoub et al. 2005)) scar keloids

(Yang et al.2003; Gira et al.2004); pyogenic granulomas;

blistering disease (Brown et al.1995); Kaposi's sarcoma in AIDS patients

(Barillari and Enzoli 2002); systemic sclerosis (Distler et al. 2004)

Adipose tissue Obesity (angiogenesis induced by fat diet); weight loss by angiogenesis inhibitors; anti-VEGFR2 inhibits preadipocyte differentiation via effects on ECs (Fukumura et al 2°°3); adipocytokines stimulate angiogenesis (Shibata et aL 2004)) Eye Persistent hyperplastic vitreous syndrome (loss of Ang-2

(Hackett et al. 2000; Gale et al. 2003) or VEGF^ (Stalmans et al. 2002))

diabetic retinopathy; retinopathy of prematurity (Campochmro 20°4); choroidal neovascularisation (CamPochiaro 2°°4) (TIMP-3 mutation (Qiet al.2003)) Bone, joints Arthritis and synovitis

(Arima et al. 2005; Lainer and Brahn 2005; Szekanecz et al. 2005; Taylor and Sivakumar 2005) ;

osteomyelitis (Hausman and Rinker 2004); osteophyte formation

HIV-induced bone marrow angiogenesis (Patsouns etal 2°°4)

Table 1 (continued)

Organ Disease in mice or humans

Primary pulmonary hypertension (BMPR-2 mutation; somatic

EC mutations (Yeager et al. 2001; Humbert and Trembath 2002; Voelkel et al. 2002)).

asthma(Bai and Knight 2005), nasal polyps (GosePath et aL2005) ; rhinitis (Kirmaz et al.2004); chronic airway inflammation (Baluk et aL 2005), cystic fibrosis (Shute et aL 2003)

Inflammatory bowel disease (ulcerative colitis (Konno et aL 2004));

liVer cirrhosis (Ward et al. 2004; Fernandez et al. 2005; Medina et al. 2005)

Endometriosis (Hu11 et aL 2003; Groothuis et al.2005) ; uterine bleeding, ovarian cysts (Abd el Aal et al.2005) ; ovarian hyperstimulation (LeCouter et aL2001) Diabetic nephropathy (Yamamoto et al. 2004; Schrijvers et al. 2005)

BMPR-2, bone morphogenic protein-2

(Van Belle et al. 1997; Waltenberger 2001; Tepper et al. 2002), whereas hypertension causes microvascular rarefaction (Boudier 1999). Reduced angiogenic signalling causes pulmonary fibrosis (Koyama et al. 2002) and emphysema (Kasahara et al. 2000). The delayed healing of gastric or aphthous oral ulcerations has been attributed to the ability of invading pathogens to produce angiogenesis inhibitors-in particular after Helicobacter pylori infections (Jenk-inson et al. 2002). Besides its vascular activity, vascular endothelial growth factor (VEGF) is also trophic for nerve cells, cardiac muscle fibres and lung epithelial cells, further explaining why insufficient VEGF levels contribute to cardiac failure, respiratory distress and motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis (Table 2). At present, angiogenesis has been implicated in more than 70 disorders, and the list is ever-growing.

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