Angiogenesis and hypertension: an update

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Aug 13, 2009 - The purpose of this review is to provide a basic understanding of the important relationship between microvascular remodelling, angiogenesis ...
Journal of Human Hypertension (2009) 23, 773–782 & 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00 www.nature.com/jhh

REVIEW

Angiogenesis and hypertension: an update R Humar, L Zimmerli and E Battegay Division and Research Unit of Internal Medicine, University Hospital, Zurich, Switzerland

The purpose of this review is to provide a basic understanding of the important relationship between microvascular remodelling, angiogenesis and hypertension, that is, provide an overview of recent experimental and clinical evidence from anti-hypertensive and pro- and anti-angiogenic therapy with respect to hypertension and microvascular structure. Microvascular rarefaction, that is, a loss of terminal arterioles and capillaries, is found in most forms of human and experimental arterial hypertension. This further increases peripheral resistance, and aggravates hypertension and hypertension-induced target organ damage. In some cases with a genetic predisposition, hypertension is preceded by a loss of microvessels. Therefore, new therapies aimed at reversing microvascular rarefaction potentially represent candidate treatments of

hypertension. The microvasculature is formed by the continuous balance between de novo angiogenesis and microvascular regression. Imbalanced angiogenesis, in addition to functional shut-off of blood flow, contributes to microvascular rarefaction. Numerous clinical trials assessing anti-angiogenic agents in cancer patients show that this therapy leads to microvascular rarefaction and causes or aggravates hypertension. The development of specific pro-angiogenic treatment to correct hypertension or ischaemic disorders, however, it is still in its infancy. On the other hand, long-term treatment by classic anti-hypertensive therapies that present vasodilator activity can correct for hypertension-associated rarefaction in man. Journal of Human Hypertension (2009) 23, 773–782; doi:10.1038/jhh.2009.63; published online 13 August 2009

Keywords: angiogenesis; vascular rarefaction; vascular peripheral resistance; endothelial dysfunction

Introduction Blood vessels are capable of structural alteration over time in addition to the acute changes in tone. Restructuring includes an increase in vascular mass—vessel wall thickening, enlargement or dilation—and alteration in capillary density, that is microvascular rarefaction. Angiogenesis and vascular remodelling represent two aspects of a series of events that determine the structure and arrangement of vascular beds: the angiogenic process gives rise to new microvessels and the remodelling process leads to structural changes in the vessel or the loss of microvasculature. Microcirculation has an important role in the pathophysiology of hypertension. Peripheral resistance is determined primarily by small arteries (150–300 mm diameter) and arterioles (10–150 mm diameter). The disappearance of capillaries and pre-capillary arterioles, a phenomenon known as microvascular (capillary) rarefaction, is a hallmark of hypertension. During hypertension capillary endothelium loses function, microvessels become constricted and unperfused and eventually disappear. Also, impaired angiogenesis leads to an Correspondence: Professor E Battegay, Division of Internal Medicine, University Hospital, Zurich CH-8091, Switzerland. E-mail: [email protected] Received 10 March 2009; revised 10 June 2009; accepted 30 June 2009; published online 13 August 2009

underdeveloped microcirculatory system during development in the first place and predispose to hypertension in later life. Microvascular rarefaction increases peripheral resistance in the microcirculation, thereby reducing blood flow and reserve and further elevating blood pressure. These are major contributing factors to the clinical complications of hypertension, such as myocardial ischaemia, stroke and end-organ damage. This cycle is well documented in several animal models of hypertension. In humans, capillary rarefaction has been demonstrated in essential hypertension and genetically predisposed individuals by using in vivo capillaroscopy of the nail fold and skin microvasculature, and by displaying changes in the retinal microvasculature. Several areas of research have led to new insights into the interactions between microvascular rarefaction and hypertension.

Microvessels contribute to vascular peripheral resistance In 1989, Greene et al.1 quantitatively estimated the relative contribution of arteriolar rarefaction and arteriolar constriction to the increase in total peripheral resistance and changes in patterns of flow distribution that are observed in hypertension. A mathematical model of the hamster cheek pouch intraluminal microcirculation was constructed, and

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then rarefaction and constriction of third-order and fourth-order arterioles were performed separately on the model. Results were quantified on the basis of the changes in the computed vascular resistance. The maximum increases in resistance in the model runs were 21% for rarefaction and 75% for constriction. Rarefaction, but not constriction, had a major effect on the degree of heterogeneity in blood flow in various vessel orders. These results demonstrated that, at least hypothetically, vessel rarefaction significantly influences tissue blood flow resistance to a degree that is comparable to vessel constriction. Moreover, unlike constriction, microvascular rarefaction markedly altered blood flow distribution.1 The small diameter of microvessels particularly affects flow resistance, which increases by the fourth power when the diameter decreases, as described for slow viscous flow by the Hagen– Poiseuille law. However, investigations in small microvessels under physiological conditions in vivo revealed an unexpectedly high flow resistance; flow resistance in 10-m microvessels at normal haematocrit exceeded flow resistance in a glass tube of corresponding diameter approximately four times.2 This increase may be related to interactions between blood components and the inner vessel surface, which might increase local viscosity or create turbulent flows.2 Up to 30% of total peripheral flow resistance is generated while passing the microvasculature as compared with 45–50% when blood passes terminal arteries and arterioles. Capillary endothelial cells may contribute to capillary constriction.3,4 Many vasoactive chemicals induce reorganization of the endothelial microfilament system and cell surface area. Ischaemia reperfusion causes focal narrowing along the capillaries, which is consistent with constriction. In isolated rat hearts, this reduction in capillary diameter is blocked by preventing F-actin re-polymerization by phalloidin.5 This implies that the contractile properties of microvascular endothelial cells may also potentially contribute to the regulation of blood pressure.5 All of this information together indicates that microvessels do contribute to peripheral resistance because of high flow resistance and microvascular rarefaction, and possibly also because of microvessel contractility.

The microvasculature is rarefied in hypertension After hypertension develops, microvascular rarefaction emerges or worsens over a short time interval. For example, rats that are made hypertensive through surgical reduction of renal mass and the administration of a high salt intake develop endothelial damage, followed by rarefaction within 3 days.6 The primary structural alterations in these Journal of Human Hypertension

microvessels appear to involve a loss of vessel integrity due to dissociation of the endothelial and smooth muscle components of the arteriolar wall.6 In patients with essential hypertension, also structural disappearance rather than functional shutting of microvessels reduces the density of capillaries in the skin of the dorsum of the fingers.7,8 Vice versa, we may detect functional, but not structural capillary rarefaction in patients with mild blood pressure elevation.9 Microvascular rarefaction can be a primary event10 because remodelling of resistance arteries and microvessels can be totally11–13 or partially14 independent of blood pressure. Patients with borderline essential hypertension have skin capillary densities that are as low or even lower than those in patients with established hypertension.15 Moreover, impaired microvascular vasodilatation and capillary rarefaction are associated with a familial predisposition to essential hypertension.16 Normotensive offspring of individuals with essential hypertension have fewer capillaries on the dorsum of their fingers.17 Therefore, impaired angiogenesis during development or early in life might predispose to high blood pressure.16 In addition, deficient embryonic vascular development, low birth weight18 and impaired postembryonic vascular growth impede the formation of microvascular networks.19,20 Thus, capillary rarefaction mostly predates, but can also follow sustained hypertension (Figure 1). Mircovascular rarefaction also emerges with senescence. Ageing is accompanied by impaired

Figure 1 Hypertension and vascular rarefaction, a vicious circle that could be interrupted by pro-angiogenesis. Increased and untreated blood pressure harms microvessels, leads to the destruction of capillaries and accelerates the pathogenic effects of vascular rarefaction. A reduced capillary count may be genetically predetermined or a consequence of a low birth weight. This vascular rarefaction increases peripheral resistance and eventually contributes to the development of hypertension. This vicious circle could be terminated by the stabilization of vascular homeostasis and growth of new microvessels through pro-angiogenic or long-term anti-hypertensive therapy by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers.

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angiogenesis due to deficient expression of several angiogenic growth factors and receptors as demonstrated by experiments in animal models21,22–25,26 (Figure 1). The clinical consequences are detrimental during revascularization of ischaemic heart disease and during the repair of injured tissues.27 A causative link between decreased angiogenic potential and a higher incidence of hypertension in the aged population still needs to be demonstrated. Microvascular densitiy during developing hypertension has been well documented in several animal models and tissues.28–31 However, not all tissues displayed reduced microvascular densities: larger microvascular networks that were occasionally found in the mesenterium of spontaneously hypertensive rats (SHR) displayed higher vessel density as compared with similar areas in normotensive control animals.31 Hypothetically, these hypertensive microvascular networks in the rat mesentery are hypersensitive to angiogenic stimuli, whereas an overall perturbation of angiogenesis would lead to rarefaction in remaining tissue of the same animal.31 In an earlier study in hypertensive patients, no changes were found in capillary number in the quadriceps muscle.32 Thus, the full understanding of the microcirculation’s role in hypertension requires a continued characterization of microvascular architectures in different tissues, and during the time course of developing hypertension.31 However, it is technically more difficult to demonstrate microvascular network formation in humans in developing hypertension. The structure of small arteries in humans is studied by biopsies taken from subcutaneous fat.33,34 Capillary rarefaction in humans is studied by capillaroscopy of the nail fold microvasculature in vivo.7,10,15 Microvascular rarefaction and disadvantageous branching geometry,35,36 and a narrower arteriolar caliber37–39 are also found in the retinal microcirculation of hypertensive patients. These retinal microvascular structures in humans may be analyzed more frequently, with precision and non-invasively during developing hypertension in the future because of recent advances in retinal photography and morphometric analysis.39

Endothelial dysfunction is associated with microvascular rarefaction Besides perturbed angiogenesis, also the balance in endothelial production of vasodilating and vasoconstricting mediators is altered in hypertension. This imbalance results in an apparent decrease in endothelium-dependent relaxations and is termed ‘endothelial dysfunction’. Endothelium-dependent relaxations are impaired in hypertensive patients and in animal models of hypertension.40 The endothelial dysfunction that is observed in hypertension appears to be a consequence of high blood

pressure because a variety of anti-hypertensive treatments normalize these responses. Therefore, endothelial dysfunction in hypertension is sometimes specified as ‘secondary’.40 Reduced bioavailability of nitric oxide (NO) and accordingly, an impairment of endothelial NO-dependent vasodilation, appears to be the key process through which endothelial dysfunction is manifested.41 Nitric oxide formation is also a prerequisite for angiogenesis to occur (for specific review see Luque Contreras et al.42). A strong local vasodilation precedes the outgrowth of endothelial sprouts and marks the first steps of angiogenesis.43 The absence of the NO pathway (either as a result of pharmacological inhibition or gene disruption of endothelial NO synthase (eNOS) prevents ischemia-,44 portal hypertension-45 or bFGF-46,47 induced angiogenesis. Furthermore, decreased levels of endothelial NO synthase and inducible NOS inhibit neovascularization in animal experiments thatuse sponge implants in young versus aged mice48 or in myocardial angiogenesis in vitro.49 Ischaemia-induced angiogenesis is generally impaired in cardiovascular diseases associated with decreased NO synthesis.42 In line, exogenous supplementation of NO by NO-donors restores ischaemia-induced angiogenesis in in vivo and in vitro models.44,50 Thus, endothelial dysfunction in hypertension may contribute to decreased angiogenic capacity of capillaries because of an impairment of NO bioavailability.42,46

Anti-angiogenic therapies can cause hypertension Angiogenesis does not initiate malignancy but promotes it, such as in tumour progression and metastasis. Many angiogenesis inhibitors that target newly forming microvessels in tumours are currently in clinical trials of all phases. At present, inhibitors of the vascular endothelial growth factor (VEGF) pathway are the most clinically advanced; bevacizumab, a humanized variant of a murine antiVEGF-A monoclonal antibody, is the only approved anti-angiogenic treatment for cancer therapy to date. Paracrine signalling through the VEGF receptor-2 pathway is essential for developmental and pathological angiogenesis, and its role in the formation and maintenance of blood vessels, tumour development and metastasis has been studied extensively.51–53 Endogenous VEGF produced by endothelial cells is also crucial for vascular homeostasis.54 Thus, existing microvessels may be harmed by therapeutics that target VEGF also, which might result in vascular rarefaction and, consequently, hypertension in subjects with no predisposition to hypertension. Indeed, several angiogenesis inhibitors have now been implicated in the development of hypertension.55–57 A meta-analysis of randomized controlled trials of patients with cancer that were Journal of Human Hypertension

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treated with bevacizumab (1850 patients from seven trials) revealed a significant dose-dependent increase in risk of hypertension.58 In early studies with bevacizumab, hypertension was seen in 22% of cases, compared with 8% in control groups. Stage 3 hypertension was seen in 11% of the bevacizumabtreated cohort.59 In a recent study in 20 patients, bevacizumab treatment-induced hypertension was accompanied by endothelial dysfunction and capillary rarefaction; both changes are closely associated with and could be responsible for the rise in blood pressure that was observed in most patients.60 Bevacizumab targeted not only the pathological and ‘switched’ vessels feeding the tumour area, but also the ‘normal’ arterioles and capillaries far from the tumour zone in patients from that study.60 Similarly, Telatinib, a multi-growth factor kinase inhibitor, caused hypertension, microvascular rarefaction and changed microvascular characteristics in patients with advanced solid tumours in a recent clinical phase-I trial.61 However, whether the observed rarefaction is structural (capillaries not present) or functional (that is, presence of nonperfused existing capillaries) is unclear. It remains uncertain whether the changes in response to anti-angiogenic therapy in microvessel architecture are reversible. Still, after cessation of anti-angiogenic therapy, blood pressure usually normalizes60 or is controllable with angiotensinconverting enzyme inhibitors (ACE-I) and in more severe cases, calcium channel blockers medication.62,63 More recently, vascular destabilizing agents are being tested, which act preferentially on the mature tumour vasculature. These agents cause a rapid stasis of blood flow in the tumour core after its administration.64 Here, the inherent differences between tumour blood vessels and the blood vessels that are associated with normal tissue make the tumour vasculature a unique target.64,65 A tumourvasculature-selective treatment of malignant disease may possibly avoid hypertension as an adverse effect. Thus, inhibiting angiogenesis is a promising strategy for the treatment of cancer and other disorders, including age-related macular degeneration. An additional insight gained is that antiangiogenic therapy leads to microvascular rarefaction and causes or aggravates hypertension (Figure 1).

Pro-angiogenesis might reduce the development of hypertension Angiogenesis counterbalances rarefaction in hypertension is (Figure 1). During angiogenesis, preexisting cells proliferate and migrate to form a new vessel in response to angiogenic molecules and hypoxia that results from tissue injury. Journal of Human Hypertension

Therapeutic angiogenesis, that is, promoting new vessel growth to treat ischaemic disorders is important for virtually all strategies to re-grow or engineer new tissue and is an exciting frontier of cardiovascular medicine. However, pro-angiogenic therapy is still in its infancy. None of the larger placebo-controlled trials, where single angiogenic growth factors were tested in patients with myocardial or limb ischaemia, have yielded convincing positive results so far.66,67 Overall, suboptimal delivery and incorrect targeting may have led to these disappointing results.68 Single growth-factor therapy leading to induction of mature, persistent and functional vessels in vivo works only when its release is precisely timed.69 This can be achieved by the incorporation of angiogenic molecules into carrier devices, such as natural or synthetic polymers or timed release of the triggers by implantable minipumps.70 Likewise, an intervention that controlled the level of VEGF in the microenvironment by using the implantation of engineered myoblasts converted pathological angiogenesis into therapeutic angiogenesis in mice.71 Combinations of several angiogenic factors induce a more secured and stable vasculature than the administration of single growth factors.72 This concept has been tested recently in a clinical phase-I trial by introducing the pro-angiogenic transcription factor hypoxia-inducible factor 1a, which is expected to activate all genes needed for proper microvessel growth.73 Infusion of bonemarrow-derived mononuclear cells is a promising possibility for inducing coordinated microvessel growth. Endothelial progenitor cells from this source assist the angiogenic process indirectly by secreting a variety of factors that induce angiogenesis, vasculogenesis or vasodilation, and stem/ progenitor cell mobilization and recruitment, or reduce apoptosis.74 Direct endothelial progenitor cell contributions to neovascularization occur through differentiation into endothelial cells or transdifferentiation into vascular smooth-muscle cells and cardiomyocytes to form the structural components of capillaries, arterioles and the myocardium.75–77 Clinical investigations of endothelial progenitor cells for regenerative medicine are now under way.78 Theoretically, therapeutic angiogenesis might also be administered as an anti-hypertensive therapy. In animal models, a direct link between blood pressure reduction and microvessel formation has been demonstrated. An engineered variant (COMP-Ang-1)79,80 of angiopoietin-1, a potent angiogenic growth factor, was tested to enhance endothelial protection and microvessel density in SHR.81 COMP-Ang-1 reduced microvascular rarefaction and tissue damage in the heart and the kidney and, intriguingly, also prevented the development of hypertension. These effects on systolic blood pressure disappeared when SHRs were pretreated with soluble Tie2 receptor,

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suggesting that the therapeutic effects of COMPAng-1 were mediated by the endothelium.81 Hypoxia served as the main trigger for angiogenesis, in a recent study, in SHRs.82 Chronic normobaric hypoxia (10% O2) decreased vascular resistance and, subsequently, systolic blood pressure by 26% already after 3 weeks when compared with normoxia (21% O2).82 Treatment with neutralizing VEGF-A antibody abrogated hypoxia-induced angiogenesis and subsequently worsened arterial hypertension. Thus, chronic hypoxia activates VEGF-A-induced angiogenesis, and thereafter prevents or normalizes microvascular rarefaction and the occurrence of hypertension.82 These are first experimental studies in animals to demonstrate that reversing microvascular rarefaction by angiogenic triggers could be a new way of treating hypertension and target organ damage (Figure 1). A normobaric oxygen content of 10%, which was used in the study by Vilar et al.82 corresponds to an altitude of approximately 5000 m, which is close to the altitude of the highest permanent human

habitation—La Rinconada, a mining village in southern Peru at almost 5100 m. Indeed, persons living in Peruvian communities at altitudes over 4000 m very rarely suffer from particularly systolic hypertension when compared with those living at sea level, as detected by a study conducted in more than 7000 persons 40 years ago.83

Established anti-hypertensive therapies may reverse microvascular rarefaction Pro-angiogenic therapy that is designed specifically to reduce blood pressure in hypertensive patients has not been addressed thus far. Clinical studies in hypertensive patients have focused mainly on blood pressure lowering, vasodilation and vasoconstriction, vascular rheology, vascular stiffness and reversal of target organ damage. However, a few clinical studies have explored the effects of anti-hypertensive drugs on the microvasculature. Indeed, effective and long time anti-hypertensive

Figure 2 (a) Angiotensin-converting enzyme (ACE) inhibition can reverse microvascular rarefaction. ACE inhibition causes bradykinin (BK) to accumulate that increases pro-angiogenic inducers such as nitric oxide (NO) and vascular endothelial growth factor (VEGF) mainly by the BK type 2 receptor and its interaction with the VEGF receptor 2.50,88,92 Also angiotensin II can be pro-angiogenic through the angiotensin type 2 receptor, which increases BK levels.103 Angiotensin type 2 receptor may be specifically activated when angiotensin II type 1 receptor blockers (ARBs) block binding to the angiotensin type 1 receptor. (b) Vasoactive peptides stabilized by ACE inhibition induce endothelial sprouts in vitro. BK, BK1n agonists and ACE inhibition by enalapril induce the outgrowth of capillary sprouts from pieces of mouse hearts cultured in a fibrin gel under hypoxic conditions. The extent and morphology of endothelial sprouts is comparable to those induced by VEGF.50 Journal of Human Hypertension

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treatment normalized vascular structure and reversed microvascular rarefaction in hypertensives. Capillary density in non-diabetic hypertensive patients increased compared with that in untreated patients.84 Furthermore, the ACE-I lisinopril reduced retinal microvascular rarefaction after 52 weeks of treatment in previously untreated hypertensive patients.35 The regenerative effect of anti-hypertensive treatment appears to be specific for the type of drugs used: ACE-I, but not b-blockers, normalized the structure of small subcutaneous arteries and arterioles of patients with essential hypertension after a 12–month treatment.85,86 Thus, the ability of anti-hypertensive agents to normalize microvascular structure may be restricted to drugs that present vasodilator activity, such as ACE-I, excluding drugs that lower blood pressure through a reduction in cardiac output, such as b-blockers.84 The pro-angiogenic effects of ACE-Is on the microvasculature have been extensively studied in experimental animal and in vitro models: ACE-Is increased myocardial capillary density in SHRs,12 in hind limb ischaemia of rabbits,87 of mice88,89 and in different rat models of obesity (Figure 2a, for specific review see Battegay et al.90). Inhibition of the breakdown of bradykinin (BK) and consecutive angiogenic activity of BK rather than angiotensin-IImediated effects most likely accounts for ACE-Itriggered angiogenesis (Figures 2a and b). Knockout of the BK B2 receptor blunted ACE-I-induced vascularization of mouse ischaemic legs88 and vascularization in an in vitro model of the hypoxic heart.50 Figure 2b depicts angiogenic activity in vitro of BK, BK1 agonist and the ACE-I enalalpril from this study.50 Further studies in rat models suggest that ACE-I-induced neovascularization depends on both BK B1 and B2 receptors.12,91,92 The ACE-I captopril represents an exception to the ‘rule’ that ACE-Is are generally pro-angiogenic: captopril, with its reactive sulfhydryl group, inihibits metalloproteinases93 and increases the formation of the endogenous and potent angiogenic inhibitor angiostatin.94 Captopril reduced microvascular growth in hypertensive and normotensive rats95 and the capillary-fibre ratio in ischaemic hind limbs of rats.96 ACE-Is, which differ from captopril chemically, however, do not possess these specific anti-angiogenic properties. The anti-hypertensive drug class of angiotensin II type 1 receptor blockers also present vasodilator activity and can increase capillary density. The angiotensin II type 1 receptor blocker losartan,97–99 but not valsartan,100 increased microvessel density in rat models of hypertension and cardiac failure. In a study in 70 hypertensive patients, losartan also reduced vascular rarefaction and hypertrophy and improved insulin sensitivity after 3 years of treatment, compared with the b-blocker atenolol.101 In line, in SHR, the angiotensin II type 1 receptor blocker olmesartan improved insulin signalling and Journal of Human Hypertension

prevented microvascular rarefaction in the skeletal muscle;102 thus, theoretically, restored insulin signalling may also contribute to vascular proliferation and angiogenesis. Taken together, these data suggest that the angiotensin II type 1 receptor blockers losartan and olmesartan, but not valsartan exert angiogenic effects and improve microvessel integrity.

Conclusion The review of results from experiments in animal models of hypertension, leads us to conclude that microvascular normalization and the abrogation of microvascular rarefaction can likely improve hypertension and hypertension-induced target organ damage. Furthermore, numerous, large clinical studies of human cancer patients who are being treated with anti-angiogenics also suggest a reciprocal proportionality between the number of functional microvessels and hypertension. However, pro-angiogenic therapy for the treatment of ischaemic peripheral and cardiac diseases is still in its infancy and is far from being used as new therapy to treat essential hypertension. The mechanisms and means of inducing microvessels safely are currently being explored, developed and assessed in clinical trials. It remains to be shown if blood pressure changes in the outcomes of these trials will match alterations in microvascular densities. At present, the only available method for normalizing or increasing the microvasculature in hypertensive patients is through long-term antihypertensive treatment. Drugs, that have a potent anti-remodelling effect or the potential to induce microvessels, particularly the non-captopril class ACE-I such as lisinopril or enalapril and potentially angiotensin II type 1 receptor blockers like losartan, might be desirable to treat hypertension, specifically when structural rarefaction precedes the onset of hypertension. It is important to understand better the mechanisms of microvascular rarefaction. Further studies on the genetics of impaired angiogenesis during development should add to our understanding of the predisposition to hypertension. A continued characterization of angiogenic responses and changes of microvessel network patterns in different tissues and those that occur over the time course of treated or untreated hypertensive disease are necessary. Here, new non-invasive diagnostic tools such as the analysis of retinal microvessels may offer new prospects.

Conflict of interest The authors declare no conflict of interest.

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