Introduction {#Sec1}
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The German ophthalmologist Leber observed and described the clinical picture of Retinal Vein Occlusion (RVO) \[[@CR1]\] about 150 years ago. RVO is the second most common retinal vascular disorder often leading to severe loss of visual function. Roughly, RVOs has been classified as follows: The central retinal vein occlusion, the hemicentral retinal vein occlusion and the branch retinal vein occlusion (BRVO) \[[@CR2]\], the latter being the most common type. Although the mechanisms involved might be basically similar in all these types, we shall focus here on BRVOs.

Until today, various pathogenetic mechanisms have been described. Nevertheless, they all leave a number of questions open.

The purpose of this paper is to summarize these unanswered questions and to formulate a new hypothetic concept considering these facts.

Present pathogenetic concepts {#Sec2}
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Mechanical compression of the vein {#Sec3}
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One of the first factors observed by Leber was both, the local relationship of BRVOs to arteriovenous A/V crossings and the association with atherosclerosis. It was assumed that the vein is compressed by the rigid artery \[[@CR3]\]. It was hypothesized that the over-crossed vein had no space to escape the pressure of the thickened and atherosclerotic altered artery and is compressed or that the vein becomes curved under the pressure of the artery. Both would lead to a disturbed blood flow and to a thrombosis. A common adventitia could fortify this effect \[[@CR4], [@CR5]\]. The concept of mechanical compression is supported by the observation that in case of BRVO, the artery crosses more often anterior rather than posterior to the vein \[[@CR6]--[@CR8]\].

Indeed, in patients with atherosclerosis and systemic hypertension, a narrowing of the vein at the A/V crossing and signs of turbulence of the blood flow are also visible in fluorescence angiographies \[[@CR9]\]. Further, multiple crossings or loops as potential causes of an occlusion have been described \[[@CR10]\]. The association of glaucoma with RVOs \[[@CR11]\] supports an IOP induced mechanical compression of the vein.

Finally, the so called sheathotomy is also based on the idea of a mechanical compression and indeed, beneficial effects have been described in some studies \[[@CR12]--[@CR14]\].

Sick vein {#Sec4}
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A proliferation and swelling of the endothelium as well as a subintimal fibrosis has been described \[[@CR15], [@CR16]\]. A trophic alteration of the vessel wall with disruption of the blood flow followed by secondary thrombosis of the vessel lumen was postulated.

Other authors however failed to find any pathological altered veins \[[@CR17]\].

Hemorheological alterations {#Sec5}
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The following parameters have been described in literature to occur more often in RVO compared to controls: Anticoagulant proteins, activated protein C resistance, factor V Leiden mutation, antiphospholipid antibodies, anticardiolipin antibodies, platelet aggregation disorders, hyperhomocysteinemia, high plasma viscosity and others \[[@CR18]\]. Again, they have been discussed controversially.

It is unknown whether such factors can induce RVOs by themselves or if they are rather cofactors.

Open questions challenging the present concepts {#Sec6}
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The pathomechanisms described above raise some questions that are listed below: If we assume the mechanical compression of the vein being important: Why is a BRVO sometimes reversible \[[@CR19]\]?Why do BRVOs not always occur at A/V crossings \[[@CR19]\]?Why is a distinct vein compression histologically not always visible \[[@CR20]\]?Why do we only extremely rarely find a thrombus \[[@CR4], [@CR21], [@CR22]\]? And if a thrombus is present why do we find it rather downstream of A/V crossings \[[@CR23]\]? And if we assume that a thrombus is present, why is the flow not completely interrupted in fluorescence angiographies after BRVO?Why is the capillary blood flow reduced in areas not affected from BRVO \[[@CR24]\]?Why does BRVOs occur also in younger patients without any signs of atherosclerosis \[[@CR25]\]?Why can we find elevated endothelin levels even in young patients with BRVO \[[@CR26]--[@CR28]\]?Why does emotional stress seem to be sometime a trigger factor for the development of BRVO \[[@CR25]\]?If we consider a sick vein being a major cause: Why do we find a risk factor constellation similar to arterial diseases such as systemic hypertension, diabetes mellitus, older age, dyslipidemia and smoking but unlike venous diseases \[[@CR29]--[@CR32]\]?Why does the accompanying retinal edema \[[@CR33]\] respond to VEGF inhibitors \[[@CR34]\] when the edema is believed to be due to back pressure?Why is the association between systemic venous thrombotic diseases and RVO extremely low? The prevalence of venous disease in patients with BRVO is approximately 3% \[[@CR35]\].Why do we, as mentioned before, only seldom find a thrombus in RVOs?If we consider a thrombus formation to be induced by hemorheological alterations and/or alterations to the coagulation cascade: Why can BRVOs develop in patients with thrombocytopenia or under anticoagulation \[[@CR18], [@CR36], [@CR37]\]?Why are only thrombophilic factors associated with RVOs, which are risk factors for both venous thrombosis and arterial vascular disease (in other parts of the body)? Risk factors for venous thrombosis alone seem not to be important \[[@CR38]\].

The concept of functional dysregulation of the vein {#Sec7}
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We propose a venous dysregulation to be the major component for the development of RVOs. Such a dysregulation implies both inadequate vasoconstriction and increased vessel permeability. The latter, results from an impaired blood-retinal barrier.

Before we discuss this new concept, we shall describe some of the basic mechanisms for vascular regulation and dysregulation:"Like elsewhere in the body the retinal arteries and veins are highly regulated. In general the regulation of arteries has attracted more attention \[[@CR39], [@CR40]\], although veins are also highly regulated \[[@CR41]\]. Among many factors involved, two factors are of special interest in this context: Endothelin-1 (ET-1) for vasoconstriction \[[@CR42]\] and the vascular endothelial growth factor (VEGF) for vessel permeability \[[@CR43]\].The vasoactive substances are either produced locally by the endothelial cells and by the surrounding tissue or diffuse from the circulating blood to the smooth muscle cells or pericytes. The influence of these molecules depends upon the function of the blood- retinal barrier. The close relationship between artery and vein at the A/V crossing (Fig. [1a and b](#Fig1){ref-type="fig"}) facilitates the diffusion of vasoactive substances from the arterial wall directly to the vein. Fig. 1**a** Histological cut through an arterio-venous crossing in a human retina. **b** Schematic drawing. 1. Artery, 2. Vein, 3. Adventitia, 4. Vascular endothelial cell layer (*blue*)Under normal conditions (Fig. [2](#Fig2){ref-type="fig"}), the endothelial cell of the retinal arterioles and venules respectively release a small amount of ET-1 intraluminally and a larger amount abluminally influencing the local vascular tone. Due to the size of the molecule (21 amino acid peptide) and due to the biological half-life time (around 15 min), ET-1 acts mainly locally. Fig. 2Physiological condition: Endothelin-1 is produced by the endothelium of the artery and the vein. This affects mainly the underlying smooth muscle cellsIn (mostly younger) patients with primary vascular dysregulation (PVD) \[[@CR44]\] (Fig. [3](#Fig3){ref-type="fig"}), the arterial wall produces (at least under certain circumstances) an increased amount of ET-1. This increases both the ET-1 concentration in the circulating blood \[[@CR45]\] as well as the ET-1 concentration in the surrounding tissue of the artery. In extreme situations, particularly if the artery lies back to back to the vein as in A/V crossings, this may lead to a local vasoconstriction of the vein. Fig. 3Vascular dysregulation: The endothelial cells of the artery produce more Endothelin-1 than normal. The vein gets under the influence of this messenger and reacts with a vasoconstrictionSuch an assumption is supported by the fact that an obstruction of retinal vessels has been shown in animals by endothelin injections in the posterior chamber \[[@CR46]\].In atherosclerosis (Fig. [4](#Fig4){ref-type="fig"}), the endothelial cells of the arteries synthesize more ET-1 than healthy normal vessels \[[@CR47]\]. In addition, cells of the surroundings of atherosclerotic arteries and cells of the vessel adventitia also produce ET-1 \[[@CR48]\]. Both lead to an increased ET-1 concentration in the neighbouring tissue. This may lead to some constriction of the arteries but even more of the adjacent veins. Veins respond at lower concentrations to vasoconstrictive molecules than arteries \[[@CR41]\]. And in addition ET-1 stimulates arterial wall fibrosis further contributing to a narrowing of the vein. Fig. 4Atherosclerosis: Due to alterations to the arterial wall and its adventitia, Endothelin-1 is not only overexpressed in endothelial cells but also additionally produced by the cells of the adventitia and by other cells of the surroundings of the atherosclerotic arteries. As consequence, the vein constricts and in extreme situation a RVO resultsThe blood-retinal barrier is weekend by several messengers such as ET-1 or VEGF (Fig. [5](#Fig5){ref-type="fig"}) \[[@CR49]\]. Both, ET-1 and VEGF, are upregulated in hypoxic tissues \[[@CR50], [@CR51]\] as it is the case in atherosclerosis \[[@CR52]\] through a hypoxia inducible factor-1α (HIF-1α) driven cascade (see Fig. [6](#Fig6){ref-type="fig"}). These upregulations indirectly point toward a hypoxia caused by arterial dysfunction. Fig. 5Hypoxic condition: **a** Hypoxic tissue produces messengers such as VEGF leading to impairment of tight junctions and thereby weakening of the blood-retinal barrier. This leads to increased permeability of the vessels with the development of exudates, retinal edema and leakage in the fluorescence angiography. **b** Obviously other factors are involved as well. For example MMP-9 can digest the basal membrane which, together with a weakened blood-retinal barrier, even allows erythrocytes to escape the lumen of the vesselFig. 6Induction of hypoxia induced messengers: Hypoxia-inducible factor-1α (HIF-1α) is constitutively produced. In situations with a normal O~2~ concentration in the tissue, HIF-1α is hydroxylated, ubiquitinated and degraded by the proteosome. In case of hypoxia however, HIF-1α is less hydroxylated and reaches the nucleus where it promotes the expression of other factors such as VEGF, Erythropoietin or ET-1"

The concept of a functional dysregulation of the vein gives answers to the following questions {#Sec8}
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Why is a BRVO often reversible?"Because the vein occlusion has a major functional component: The resulting venous vasoconstriction might fade, for example due to a decrease of the concentration of local constricting factors. If the vessel relaxes RVO resolves partially."

Why do BRVOs not always occur at A/V crossings?"Because veins might come under the influence of vasoconstricting messengers produced by the artery and adventitia independent of an A/V crossing in areas where arteries and veins are close enough. And in fact, in these cases the occlusion occurred at a point where the artery and the vein were adjacent \[[@CR53]\]."

Why is a distinct vein compression histologically not always visible?"The mechanical vein compression might just be a cofactor in addition to the vasoconstriction described above, sometimes present, sometimes not."

Why do we only extremely rarely find a thrombus?"Because the vein occlusion may be due to a functional narrowing of the vein and a thrombus may be absent or if present it might have been developed rather secondary."

And if a thrombus is present why do we find it rather downstream of A/V crossings?"Because the thrombus formation is secondary to the functional narrowing of the vein due to hemodynamic alterations downstream to the narrowing."

And if we assume that a thrombus is present, why is the flow not completely interrupted in fluorescence angiographies after BRVO?"Because the local obstacle to blood flow is rather a venous constriction than a thrombosis. Such a constriction rarely leads to a total occlusion."

Why is the capillary blood flow reduced in areas not affected from BRVO?

Why does the blood flow often remain decreased after the recovery from a BRVO in the area of the former BRVO but also in areas that are not affected and even in the fellow eye?"We assume the primary pathology being on the arterial side leading more or less to hypoxia and upregulation of certain vasoconstrictive messengers. If the concentration of vasoactive factors normalize, the underlying arterial disease (e.g. atherosclerosis) is still present."

Why does BRVOs occur also in younger patients without any signs of atherosclerosis?

Why can we find elevated endothelin levels even in young patients with BRVO?

Why does emotional stress seem to be sometime a trigger factor for the development of BRVO?"In patients with PVD, we find a higher basal ET-1 concentration in the blood than in healthy non-PVD subjects \[[@CR45]\]. They often have systemic hypotension \[[@CR54]\].As blood pressure drops, the ET-1 sensitivity increases in subjects with PVD but not so in non-PVD subjects \[[@CR55]\].ET-1 levels increase more in these subjects in situations of emotional stress \[[@CR56]\].In young patients where other risk factors such as atherosclerosis are absent, it is probably a pure functional vasoconstriction triggering the cascade leading to the clinical picture of RVOs."

Why do we find a risk factor constellation similar to arterial diseases such as systemic hypertension, diabetes mellitus, older age, dyslipidemia and smoking but unlike venous diseases?"Because the risk factors for atherosclerosis lead to altered arteries. The endothelial cells of these arteries and the hypoxic surrounding tissues produce an increased amount of local vasoconstrictors."

Why does the accompanying retinal edema respond to VEGF inhibitors when the edema is believed to be due to back pressure?"As a consequence of hypoxia in RVOs, several factors such as VEGF might be upregulated. VEGF is known to cause an impairment of the blood- retinal barrier. As a consequence retinal edema is treatable with VEGF inhibitors."

Why is the association between systemic venous thrombotic disease and RVO extremely low?"Because a thrombus might be absent and if present it might be due to the narrowing of the vein and rarely a primary event."

If we assume a thrombus, why can BRVOs develop in patients with thrombocytopenia or under anticoagulation?"Because a thrombus formation might not be necessary for the development of RVOs. A temporal interruption of the blood flow due to a functional narrowing of the vessel might be sufficient for the development of the clinical picture of RVO."

Why are only thrombophilic factors associated with RVOs, which are risk factors for both venous thrombosis and arterial vascular disease (in other parts of the body)? Risk factors for venous thrombosis alone seem not to be important?"Because we postulate a cascade driven by ischemic tissues with a primary pathology of the arteries that secondary influences the vein. An altered arterial vessel wall as well as an hypoxic surrounding tissue might be responsible for an enhanced local endothelin production."

Does the success of sheathotomy indicate mechanical compression?"After surgical separation of the artery from the vein, the vein is separated from the artery at a larger distance and is therefore less influenced by the local messengers. In addition, vitrectomy reduces the retinal hypoxia \[[@CR57]\] and thereby reduces the production of vasoactive molecules in the surrounding tissue."

Why is RVO and glaucoma often associated?"RVO occurs more often in glaucoma patients. This can be explained by the fact that RVOs and glaucoma have some risk factors in common leading to the assumption that the two diseases may be interconnected \[[@CR58]\]. The corresponding risk factors however seem more pronounced in RVO than in glaucoma: On the molecular biological level, both in glaucoma as well as in RVOs, substances such as HIF-1α \[[@CR59]\], ET-1 \[[@CR27]\] \[[@CR60]\], VEGF \[[@CR33], [@CR61], [@CR62]\] or Erythropoietin \[[@CR3], [@CR64]\] are increased.On the more physical level, the upregulated substances may lead to both a vasoconstriction \[[@CR65]\] and a weakening of the blood-retinal barrier \[[@CR66]\]. In glaucoma the factors mentioned above diffuse from the fenestrated choroid to the optic nerve head (ONH). Therefore, vasoconstriction occurs particularly in the peripapillar region \[[@CR65], [@CR67], [@CR68]\]. The impaired blood- retinal barrier is visible as increased leakage of the ONH in fluorescence angiography \[[@CR66]\] or in extreme cases even as splinter hemorrhages \[[@CR69], [@CR70]\].The venous pressure is increased in both conditions. This can be observed by an increased ophthalmodynamometric force required inducing venous pulsation and the fewer appearance of spontaneous venous pulsations in glaucoma \[[@CR71]\] and RVOs \[[@CR72]\].On the level of aetiology, in both diseases risk factors such as an increased IOP, primary vascular dysregulation \[[@CR73]\] and sleep apnea \[[@CR74], [@CR75]\] seem to play a role. Interestingly, increased levels of ET-1 have been found in patients with PVD and sleep apnea as well as in animal models with elevated IOP \[[@CR45], [@CR76]--[@CR78]\].All these factors together sufficiently explain the relationship between glaucoma and RVO."

Conclusion {#Sec9}
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About one decade ago, we described primary vascular dysregulation (PVD) as a risk factor for glaucomatous damage. In the present paper we describe a dysregulation of the vein as a component for the pathogenesis of retinal vein occlusions.

While the pathophysiological concepts of RVOs described in the literature so far, cover some aspects of the disease, they are not totally sufficient to explain all phenomena and aspects. Our concept is based on the assumption that we are dealing less with a primary structural pathology of the vein but rather with a functional constriction of the vein. This, in turn, may be secondary due to a change of the arterial vessel wall and/or due to the hypoxic surrounding tissue. Hypoxia induces the upregulation of factors that constrict veins. They may also contribute to the impairment of the blood-retinal barrier leading to oedema and in extreme cases even to hemorrhages.

This concept also explains the relation between RVOs and other diseases including atherosclerosis, glaucoma and PVD.

Further studies are needed to confirm or reject this new concept.

Outlook {#Sec10}
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In order to prevent vein occlusions we try to predict such an event with the help of biomarkers. In the present manuscript we describe the vascular dysregulation as a major risk factor and biomarker for vein occlusions. Vascular dysregulation can be recognized based on patient's history (e.g. often cold hands and feet), on clinical examinations (e.g. reduced neurovascular coupling) or laboratory findings (e.g. altered gene expression in lymphocytes).

While we are still in an early stage in search of the relationship between vascular dysregulation and vein occlusions, more information is already available about the relationship between vascular dysregulation and glaucoma \[[@CR79]--[@CR81]\]. The identification of vascular dysregulation in glaucoma patients leads already to a more personalized therapy: Glaucoma patients with vascular dysregulation benefit e.g. from an antivasospastic therapy such as calcium channel blockers \[[@CR82]\] in addition to the standard intraocular pressure lowering therapy.

A better understanding of the pathophysiology of RVOs and more specific biomarkers related to the individual risk will bring a personalized therapy within reach.
