Angiopoietins in arterial hypertension: a mechanism of adaptation or a target for treatment?

The vascular system does not represent a rigid structure and during one's life span it undergoes a ceaseless process of renovation, regeneration and remodelling. During the stage of embryo development and the early period of life, the vascular tree grows to nurture emerging tissues. However, the ‘mature’ organism also requires modulation of its vascular architecture to adapt to the changing circumstances and cope with disorders accumulating with advanced age. Indeed, the human body is equipped with a number of ways to manage this task. Known endothelium-specific growth factors include the vascular endothelial growth factors (VEGFs), the angiopoietin (Ang) families and at least one member of the large ephrin family. Moreover, vessel formation also requires the presence of growth factors which are not exclusively endothelium-specific, such as platelet-derived growth factor, fibroblast growth factor (FGF) or transforming growth factor (TGFβ)] [1]. Additionally, bone marrow includes many cells with the potential to differentiate into cells with endothelial phenotype. To form and maintain functional vessels, all of these factors must act in a well balanced and coordinated manner. Angiopoietin-1 and vascular stability Among the members of Ang family Tie2 receptor and its ligands Ang-1 and Ang-2 have attracted much attention as factors related to angiogenesis and inflammation. Ang-1 is expressed by supporting vascular cells (e.g. pericytes) but not by endothelial cells, even when stimulated by hypoxia, VEGF or tumour necrosis factor (TNF-α) [1,2]. Important insights into the physiological roles of Ang-1 and the Tie2 receptor were initially obtained from the observations on genetically engineered animals unable to express them [2]. In contrast to mouse embryos not producing VEGF, embryos lacking Ang-1 or Tie2 develop a rather normal primary vasculature initially, but subsequently, this vasculature fails to undergo the normal remodelling process. Ultrastructural analysis demonstrates impaired links between endothelial cells lacking Tie2 receptors with the pericytes which are unable to express Ang-1 [3]. Prominent abnormalities are also seen in the hearts with ineffective links between the endocardium and myocardium, as well as impaired trabeculae formation. In models of transgenic overexpression of angiogenic growth factors VEGF, this leads to immature, leaky and haemorrhagic vessels as Ang-1 appears to be critical for vessel maturation and stabilization [4]. Of note, the overexpression of Ang-1 in skin results in pronounced hypervacularization due to a marked increase in vessel size (rather than their number) [4]. In contrast, VEGF in similar models primarily increases vessel number. Thus, Ang-1 might promote circumferential growth rather than development of new vessels per se, and suggest that key effects discriminating the role of VEGF family and Ang family are correspondently angiogenesis (i.e. growing new microvessels, for example, by their sprouting) and arteriogenesis (i.e. the development of bigger arteries from microvessels). Although the role of Ang-1/Tie2 pathways in growing tissue is angiogenic, their function in the mature body may be somewhat different, perhaps related to preservation of stability in the existent vascular network. The binding of Ang-1 to Tie2 mediates rapid receptor phosphorylation and transduction of signals through the protein kinase B–Akt pathway, hence promoting survival of endothelial cells (e.g. by inhibition of apoptosis) [5]. Tie2 activation also results in inhibition of nuclear factor (NF)-kB, thus reducing inflammatory burden [6]. Of note, Ang-1 can even inhibit excessive VEGF-induced blood vessel formation [7]. Taken together, constitutive Ang-1 expression and low-level Tie2 phosphorylation in the adult vasculature probably represents a control pathway to maintain vascular quiescence by antiapoptotic and anti-inflammatory effects, thus protecting the endothelium from excessive activation by cytokines. Angiopoietin-2 as a ‘switch’ in vascular remodelling Ang-2 shares 60% structural homology with Ang-1, and both Ang-1 and Ang-2 bind to the same site in the extracellular domain of Tie2 with similar affinities [8]. However, Ang-2 binding to Tie2 does not elicit Tie2 phosphorylation, thus acting as an antagonist ligand of Tie2 and demonstrating many opposite biological effects compared to Ang-1 [9]. In fact, mice overexpressing Ang-2 have a phenotype corresponding to Tie2-deficient or Ang-1-deficient mice [8]. Ang-2 expression, however, is tightly controlled. Ang-2 mRNA is almost undetectable in the quiescent vasculature and is detected only at those sites undergoing remodelling (e.g. in sprouting tumour blood vessels) following stimulation by different cytokines (e.g. VEGF, FGF and TNF-α) and environmental factors (hypoxia, high glucose levels and oxidative stress) [8,10]. For example, Ang-2 levels are increased in diabetic mice with myocardial ischaemia and in patients after percutaneous coronary interventions [11]. The release of Ang-2 results in rapid destabilization of the endothelium, perhaps indicative of their role as an autocrine negative regulator of the quiescent resting endothelium and as a key destabilizing signal involved in initiating angiogenic remodelling. Angiopoietin-2 functions are also dependent upon coexpression of other factors, such as VEGF. In the presence of VEGF, Ang-2 is proangiogenic and promotes a rapid increase in capillary diameter, remodelling of the basal lamina and new vessel growth [12]. In the absence of VEGF, however, Ang-2 leads to endothelial cell death and vessel regression [12,13]. Also, early atherosclerotic lesions express VEGF and Ang-1 in contrast to the advanced lesions with abnormal neovascularization, characterized by high levels of VEGF and Ang-2 [14]. Importantly, the presence of Ang-2 (but not Ang-1) is required to trigger sprouting angiogenesis, at least in the experimental setting [15]. Again, Ang-2 may be more important for the formation of coronary collaterals, compared to Ang-1 [16]. How can Ang-2 modulate sensitivity of the endothelium to cytokine stimulation? There is no clear answer to this question but inhibition of Ang-1 affects Ang-2, and this may affect the integrity of interendothelial cell contacts and junctional complexes, as well as the expression of surface receptors for the various growth factors and cytokines. Additionally, Ang-1–Tie2-independent mechanisms may be involved, although these are not known at present. In addition to the modulation of angiogenesis, Ang-2 could also influence arterial inflammatory status. For example, mice deficient in Ang-2 cannot elicit an inflammatory response and Ang-2 promotes leucocyte adhesion via activation endothelial cells by TNF-α to produce adhesion molecules. Furthermore, Ang-2 blocks the antiapoptotic effects of Ang-1. Thus, is Ang-2 a friend or enemy of a healthy vascular system? The answer may depend on clinical circumstances. A relationship between angiopoietin and hypertension? The role of the renin–angiotensin system in the pathophysiology of hypertension and heart failure has long been recognized. Stimulation of AT1 receptors activates intracellular pathways, resulting in vasoconstriction, inflammation and vessel proliferation. Angiotensin II can also induce neovascularization in experimental models via the expression of different growth factors, such as VEGF, FGF, transforming growth factor beta and ultimately, via the Ang pathway. Several studies have shown that hypertensive patients have increased plasma levels of VEGF, Ang-1, Ang-2 and Tie2 [17,18]. Enhanced production of Ang-1 has also associated with hypertensive target organ damage and an increased risk of cardiovascular events [17,18]. Also, plasma levels of VEGF in hypertensive patients correlate significantly with Ang-1, Ang-2 and Tie2 levels [17]. Of additional interest, increased Ang-2 and VEGF levels in such patients have been related to excessive platelet activation [18]. Not surprisingly, high Ang-2 concentrations are also significant predictors of myocardial infarction and stroke in hypertensive patients [19]. The implications of Ang-2 in hypertension are still to be elucidated but one may speculate that activation of this growth factor is directly related to the processes of cardiac and vascular remodelling triggered by high blood pressure [20]. Indeed, coronary angiogenesis, enhanced during the early phase of adaptive cardiac growth in experimental hypertension, has been shown to depend on Ang-2 expression [21]. In the current issue of the Journal of Hypertension, David et al.[22] have demonstrated that high Ang-2 levels persist in the circulation of hypertensive patients even despite blockade of AT1 angiotensin receptors and the administration of statins. Importantly, a chronic increase in expression of angiogenic factors may be associated with the risk of progression to heart failure. Perhaps this is unsurprising, as Ang-2 levels are known to be elevated in those who have developed heart failure and levels also correlate with left ventricular ejection fraction [23]. Of note, Ang-2 (but not Ang-1 or VEGF levels) is higher in patients with acute heart failure, when compared to those with stable chronic heart failure [23]. Additionally, multivariate analyses show a strong independent prognostic impact of high Ang-2 levels on survival in critically ill medical patients [24]. Can modulation of the angiopoietin system be beneficial? Ang-1 gene transfer to rat-infarcted hearts significantly increases capillary density and reduces infarct sizes, as well as the attenuation of cardiac dysfunction [25]. Given that Angs act in an autocrine and paracrine manner, cellular proximity and location of Ang-1-expressing cells may be important. Indeed, the implantation of Ang-1-expressing skeletal myoblasts results in a superior angiogenic response and the improvement of cardiac contractility, when compared to direct adenoviral Ang-1 injection in animal model of myocardial infarction [26]. In the human setting, the treatment of hypertension significantly reduces Ang-1 levels [17]. The study by David et al.[22] provides evidence that in contrast to the effects on Ang-1, the inhibition of the renin–angiotensin system may not have a significant impact on Ang-2 levels. The authors further demonstrate that significant anti-inflammatory activity related to an angiotensin receptor blocker was not mediated by the Ang pathway. The study by David et al.[22], however, raises a number of important questions. What do high levels of Ang-2 indicate, perhaps ongoing remodelling and enhanced angiogenesis? Is the increased Ang-2 production in hypertensive patients counterbalanced by sufficient Ang-1 expression? Which mechanisms are responsible for reduction of inflammatory burden following blockade of AT1 receptors? Does Ang-2 represent a marker of persisted endothelial activation in arterial hypertension independent of blood pressure levels? Even more importantly, does excessive Ang-2 production represent a novel target to prevent hypertensive target organ damage, the subsequent development of heart failure or to reduce the risk of cardiovascular complications in patients with arterial hypertension? Clearly further studies are warranted to address these important issues.