Current Vascular Pharmacology, 2004, 2, 000-000 1 1570-1611/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. Angiotensin II, Cell Proliferation and Angiogenesis Regulator: Biologic and Therapeutic Implications in Cancer Elizabeth Escobar 1 , Tatiana Sofía Rodríguez-Reyna 1 , Oscar Arrieta 1,2,* and Julio Sotelo 1 1 Neuroimmunology Unit, National Institute of Neurology and Neurosurgery of Mexico and 2 UNAM, Mexico City, Mexico Abstract: Angiotensin II (ANG II) is the main effector peptide in the renin-angiotensin system. It is generated by the activation of Angiotensin I through the Angiotensin II Converter Enzyme (ACE II). ANG II has multiple physiologic effects that regulate vascular tone, hormone secretion, tissue growth and neural activity. It has systemic (endocrine) and local (paracrine and autocrine) effects, favoring cell growth and differentiation through four types of receptors from which types 1 and 2 (AT 1 and AT 2 ) are the most important. Stimulation of AT 1 leads to the activation of intracellular pathways that finally lead to vasoconstriction, inflammation and proliferation. The AT 2 receptor is mainly expressed in fetal tissue and scantly in the cardiovascular system under different circumstances. Its effects are opposite to those of the AT 1 . The stimulation of AT 1 activates second messengers that lead to a rapid production of diacylglycerol and 1-4-5-inositol triphosphate, as well as to the activation of C protein. Several reports indicate that ANG II can induce neovascularization in experimental systems due to the expression of different growth factors such as angiopoietin 2, vascular endothelial factor, and its receptor, fibroblast growth factor, platelet derived growth factor, transforming growth factor β and epidermal growth factor. Other mechanisms associated with ANG II induced angiogenesis are nitric oxide synthase and metalloproteinase expression, as well as inflammation induction. Angiogenesis is a fundamental process to tissue repair and development, and it participates in several pathologic processes. In Addition, the AT 1 receptor is expressed in many malignant neoplasms and its blockade through ECA II inhibitors and ANG II antagonists has shown antineoplastic activity as well as angiogenesis inhibition in tumoral experimental models. This review discusses the mechanisms by which ANG II participates in neoplastic and non-neoplastic tissue angiogenesis and its possible therapeutic implications. Key Words: angiotensin, cancer, angiogenesis, apoptosis, AT 1 , growth factors. 1. OVERVIEW OF THE ANGIOTENSIN II SYSTEM ANG II is a peptidic hormone. It is the main effector in the renin-angiotensin-aldosterone system (RAAS), one of the most powerful vasoconstrictor systems of the body [1]. The activity of this system starts with the release of renin from the juxtaglomerular cells in the kidney, where renal ischemia is one of the main activators of the system. Renin acts as an enzyme on angiotensinogen or plasmatic substrate, an α globulin synthesized by the liver. This catalytic reaction cleaves the amino terminal residue of the decapeptide generating ANG I, an unstable peptide that is quickly cleaved by ECA II into ANG II [2-4]. RAAS has an important role in the regulation of blood pressure and liquid and electrolyte balance; it participates in the pathophysiology of hypertension and its complications (cardiac hypertrophy, remodeling and nephropathy), coronary artery disease, heart failure and renal failure [1, 5]. The final responses to the activation of this system are different in every tissue, inducing vasoconstriction in smooth vascular muscle, release of aldosterone in adrenal glands, gluconeogenesis in the liver, sodium absorption in intestine *Address correspondence to this author at the National Institute of Neurology and Neurosurgery of Mexico, Insurgentes Sur 3877, 14269 Mexico City, Mexico; Tel: (525)-606-4040; Fax: (525)-528-0095; E-mail: ogar@servidor.unam.mx and kidneys, increased fibroblast growth in the heart, increased β-adrenergic activity in the nervous system and increased thirst [6]. ANG II was initially described as a vasoconstrictor peptide but recent studies have revealed that ANG II acts also as a growth factor. ANG II plasmatic levels modulate contraction, cell growth, apoptosis and cell differentiation, and it has a role in cell migration, extracellular matrix conformation, inflammation and stimulation of the production of several growth factors as the platelet derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor beta β (TGFβ), insulin like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) [7-13] and platelet activator factor (PAF). It also stimulates the production of some vasoconstrictors as endothelin 1 (ET-1) and it helps to transactivation of growth factor receptors (EGF receptor and IGF receptor) [14]. Besides, it induces the expression of several proto-oncogenes in smooth vascular muscle in rats and humans, including c-fos, c-jun, c-myc, erg-1, VL-30, and the activator of the protein 1 complex [ 15, 16]. At present time, ANG II is known as a regulator of proliferation and hypertrophy of vascular smooth muscle cells, acting as a bifunctional apoptosis modulator through its receptors: AT 1 (antiapoptotic) and AT 2 (proapoptotic) [17].