Worldwide, glaucoma is the second most common cause of blindness. If detected early, it can be well treated. But glaucoma develops for a long time without symptoms, so as a person affected you will not notice anything until it is too late for help and you go blind. A study by the University Medical Center Mainz (Germany) on the pathogenesis and pathophysiology of glaucoma found that the tissue hormone angiotensin II plays a role in the development of the eye disease. This finding of the Mainz research team could influence the diagnosis and therapy of glaucoma in the future. Detailed results of the study have been published in the journal Redox Biology.
The causes for the development of glaucoma are manifold and the symptoms are very different. Although elevated intraocular pressure is still one of the most important risk factors, it is insufficient as the sole diagnostic or prognostic factor: In approximately 30 percent of all patients who have already developed glaucoma damage, elevated intraocular pressure could never be measured. In the development of glaucoma, vascular conditions related to the blood supply to the eye also appear to be significant in all cases.
This is because the visual organ is metabolically very active. Despite its small size, it has a much higher energy metabolism than the brain, for example. Many studies have shown that anomalies in the regulation of blood flow are associated with the development of glaucoma. One of the most important blood flow-regulating systems is the renin-angiotensin system (RAS), which increases blood pressure in low blood volumes by releasing the tissue hormone angiotensin II. A study on microvessels and retinal tissue isolated from mice, published in the journal Redox Biology by the Eye Clinic and Polyclinic of the University Medical Center Mainz, now sheds light on the subject using optimized measurement methods. The team led by Dr. Caroline Manicam and Dr. Natarajan Perumal was able to show that angiotensin II triggers oxidative stress in two crucial microvascular beds of the eye, that of the ophthalmic artery and that of the retina. This work is a joint effort of the Department of Ophthalmology with the participation of Prof. Dr. Marianne Müller and Dr. David Herzog in an effort to better understand the pathomechanisms underlying this neurodegenerative disease.
The Chairman of the Board of Directors and Medical Director as well as Director of the Eye Clinic and Polyclinic of the University Medical Center Mainz, Prof. Dr. Norbert Pfeiffer, sees the newly established model as an excellent addition to the glaucoma models at the Eye Clinic, which up to now have mainly focused on investigations of intraocular pressure. "This new in vitro model depicts further facets of the disease, which is one of the most common causes of blindness. Using this model, we can now investigate different causes of the disease and try to develop new therapies for the treatment of glaucoma, in particular normal-pressure glaucoma," said Prof. Dr. Norbert Pfeiffer. "I am particularly pleased, along with the two junior scientists who are mainly responsible for the project, that the publication has gone through the review process required for a scientific publication without the need for a revision associated with further experiments and was therefore able to appear very quickly. This speaks for the extraordinary quality of this publication and the scientific work of the entire team," he added.
The chosen in vitro approach had the advantage that the molecular processes could be observed independently of an angiotensin II-induced blood pressure increase. This measurable oxidative stress is based on changes in the composition of the proteome and signal transduction pathways, which the authors investigated for these small amounts of tissue using adapted methods mass spectrometry and quantitative real-time PCR. "In the meantime, mass spectrometric proteome analysis in particular has developed into a potent instrument for the precise analysis of physiological or pathological changes in molecular mechanisms," explains Dr. Natarajan Perumal.
"During our investigations, we noticed changes in various molecules which, as messenger substances, play an important role in the energy supply and metabolism of the eye and which are to be followed up in the future," adds Dr. Caroline Manicam, who is primarily responsible for this study and who had obtained the necessary financial support from the German Research Foundation (German acronym: DFG). Dr. Manicam further explained: "We also observed vascular remodeling in the ophthalmic artery, which is mediated by the actin cytoskeleton and integrin-linked kinase signaling pathways. We suspect that this affects the contractility and stability of the vessels and thus has an effect on the blood and nutrient supply to the eye and the possible development of glaucoma".
"Unfortunately, the central role of the eye's microvasculature in the pathogenesis of glaucoma has often been overlooked in favor of increased intraocular pressure. However, our investigations have now provided the first direct mechanistic insight into the signal transduction pathways driven by angiotensin II and the role of the identified proteins in the development of glaucoma. Whether the observed molecular alterations rather represent an angiotensin II-induced adaptation reaction of the two investigated vascular beds, which ensures the survival of the affected cells, or whether they have pathological consequences that might lead to glaucoma, will hopefully be shown by our next investigations," added Dr. Manicam with a positive outlook to future research projects.
Bioenergetic shift and actin cytoskeleton remodelling as acute vascular adaptive mechanisms to angiotensin II in murine retina and ophthalmic artery; Natarajan Perumal, Lars Straßburger; David P. Herzog; Marianne B. Müller; Norbert Pfeiffer; Franz H. Grus; Caroline Manicam; DOI: https://doi.org/10.1016/j.redox.2020.101597