Abstract

In the genesis and later development of age-related macular degeneration (AMD), endothelial dysfunction (ED) has a crucial role. AMD-risk factors, which play a decisive role in AMD, are in a close connection, correlate with, and often are identical wih the risk factors (RFs) of cardiovascular diseases (CVDs), so that it can reasonably be presumed that the two conditions have a similar pathogenesis. These risk factors, which seem essentially different, lead to chronic vascular injury based on the same mechanism of action: by inducing oxidative stress (OS). ED itself is a consequential-consecutive phenomenon (OS→ED!), and is a clinico-pathophysiologically important connecting link between harm(s)/noxa and vascular injury (harm [noxa] → oxidative stress (OS) → endothelial activation (EA), endothelial dysfunction (ED), respectively → vacular injury, vascular disease). Disordered function of endothelium in the vessels supplying the affected ocular structures with blood (ED) have a key role in the genesis and development of age-related macular degeneration. Changes in blood vessels including those in choroids may be triggered by several repeated and/or prolonged mechanical, physical, chemical, microbiological, immunologic, and genetic influences/impacts/noxa (in fact, the risk factors!), against which protracted response[1]**) (increased ROS formation → oxidative stress → endothelial activation/dysfunction → aftermath of EA/ED) may develop, and in consequence of this, (chronic) vascular damage (functional and then structural alteration [remodelling] of the blood vessel), pathological consecutive changes ending in AMD, ultimately, may develop (choriocapillaris degenerates in exudative AMD, choriocapillaris degeneration precedes retinal pigment epithelial atrophy in wet AMD). All this goes to show that AMD may be a local manifestation of systemic (vascular) disease, undoubtedly. AMD is the disease of the aging body. Normal aging processes can lead to structural and blood flow changes that can predispose patients to AMD. Advancing age is a privotal and independent risk factor for vascular disease as can be understood from the fact that aging individuals often demonstrate dysfunctional blood vessel repair after vascular injury and aging per se, in the absence of other risk factors is associated with oxidative/nitrosative stress and inflammatory changes in the phenotype of blood vessels (primary abnormalities in ocular perfusion worsen with age, secondarily causing dysfunction of the retinal pigment epithelial cells, predisposing eyes to AMD), these changes together with individual’s (environmental) risk factors set the stage for the development of AMD. Regarding therapy/preventive treatment/prevention of AMD: (I) Non-medicinal (preventive) treatment such as lifestyle modifications of AMD patients (modifying lifestyles behavours of diet, smoking and physical activity) is of indispensable importance; they influence strongly and very beneficially the established vascular risk factors and also advantageously affect novel pathways of risk such as inflammation/oxidative stress, endothelial function, thrombosis/coagulation. Modest alterations of these lifestyle risk factors are achievable and have substantial effects on (vascular) risk. (II) Various medicaments: (1) ACE inhibitors, (2) AR blockers [including telmisartan with its peroxisome proliferator-activated receptor-gamma |PPARgamma| agonist effect], (3) statins, (4) acetylsalicylic acid, (5) trimetazidine, (6) third generation beta blockers, and (7) PPARgamma agonists, exert a beneficial effect on endothelial dysfunction and its consequential functional, structural and metabolic disorders. The advantageous/beneficial effect of a favourable influence on the successful treatment of ED in patients with chronic vascular and cardiovascular diseases has become evidence now, as the human vascular system is uniform, consubstantial thus medicines beneficial in ED may exert a favourable effect also on the vessels of the eye, in the retina/choroid (per analogiam of cardiovascular disease). The antioxidant vitamins (AOVs) used for preventing OS, conventionally, did not really live up to the hopes placed in them. The activity of AOVs against OS is limited only to scavenging the already formed oxidative products: the inhibition of the reaction pathway peroxynitrite → DNA damage → PARP by rapid catalytic breakdown of peroxynitrite with the help of the so-called "causal"antioxidants with mitochondrial effects (FP15 metalloporphyrin compound), showing great promise, or by the inhibition of PARP with INO-100 may open a new possibility in the treatment of OS induced vascular dysfunction in several pathologic conditions including AMD.- Nevertheless, we have excellent therapeutic possibilities/options also, until then: the statins, the ACEIs, ARBs, ASA, the trimetazidin, third generation beta-blockers, PPARgamma agonists. As the human vascular system is uniform and consubstantial, thus medicines and non-medicinal methods/treatments beneficial in ED may exert a favourable effect also on the vessels of the eye, in the choroid/retina. Consequently, based on the aforementioned, it seems logical to presume that, as a part of our primary and secondary preventive activity, that such medicines should be given to: (1) patients who have no macular degeneration, but have risk factors of AMD (and of cardiovascular (CV) disease, respectively) inducing ED, and are older than 50 years; (2) patients who have been diagnosed with unilateral AMD, in order to prevent the damage of the contralateral eye due to macular degeneration; (3) and finally, patients who have been diagnosed with bilateral AMD, in order to avert deterioration and in the hope of a potential improvement. In addition, lifestyle modifications of AMD patients (modifying lifestyles behavours of diet, smoking and physical activity) is of indispensable importance. We should strive to (III) completely eliminate/treat the risk factors of macular degeneration (and ones of the CV disease) which induce OS and consequential ED, in addition.

1 **) The so-called host defense response: any kind of noxa endangering steadiness of homeostasis → increased ROS formation → oxidative stress → endothelial activation, endothelial dsfunction, respectively, in order to eliminate, avert, clear disturbing noxa

Key words: Age-related macular degeneration, endothelial dysfunction, oxidative stress, risk factors, primary and secondary prevention.