Translational research in retinal vascular disease. An approach

Abstract

The clinical presentation of the most frequent vision threatening retinal diseases is dominated by lesions indicating that disturbances in retinal blood flow are involved in the pathogenesis of these diseases. The present review describes the experience from a translational strategy pursued to investigate retinal vascular diseases with diabetic retinopathy as the main object. The normal regulation of retinal blood flow is investigated in porcine retinal vessels in vitro and ex vivo. Subsequently, the in vitro findings are translated to clinical studies in normal persons in vivo, and it is investigated whether the mechanisms are disturbed in retinal vascular disease. This is followed by clinical intervention studies on these diseases. The approach has been used to investigate pressure autoregulation, metabolic autoregulation and vasomotion in retinal vessels. The investigations have shown that retinal vascular tone can be regulated by receptor‐specific agonists and antagonists to vasoactive compounds such as purines, prostaglandins and nitric oxide synthesis and that the vasoactive effects can be modulated by the concentration and the mode of administration of these compounds. Additionally, it has been shown that retinal precapillary arterioles and capillaries not visible by ophthalmoscopy may play an important role for the pathophysiology of retinal vascular disease and its treatment. Future studies should focus on investigating normal and pathological regulation of retinal blood flow in these smaller vessels.

Reduced Oxygen Extraction in the Retinal Periphery When the Arterial Blood Pressure Is Increased by Isometric Exercise in Normal Persons

“…A similar threshold has been found in the cerebral circulation 28 and implies that minor fluctuations in the arterial blood pressure are transmitted to the precapillary arterioles that regulate recruitment and intermittency of blood flow in the microvascular units. 29 A prominent role of these smaller vessels for regulating retinal blood flow is consistent with observations in vitro 5,6,[30][31][32] and with vivo findings that increased metabolism, resulting in a 3% to 4% dilatation of the larger retinal arterioles, elicits an approximately 10 times higher increase in retinal blood flow. 4,33 In the present study, the increased arterial blood pressure can be expected to have been transmitted to the macular microcirculation since no adaptive changes were observed in diameter and oxygen saturation in the larger vessels to this area.…”

The vasoactive effects of bradykinin, vasoactive intestinal peptide, calcitonin gene‐related peptide and neuropeptide Y depend on the perivascular tissue in porcine retinal arterioles in vitro

“…However, the NO‐dependent relaxation also depended on the presence of perivascular retinal tissue. This is in contrast to observations of NO synthesis in vascular endothelial cells elsewhere in the body (Vanhoutte et al, 2016) but is in accordance with studies of hypoxia‐induced relaxation of retinal arterioles that depends on non‐endothelial NO released from the perivascular retina (Bek, 2019; Hansen et al, 2015). This points to inducible NO as a final common mediator for relaxation of retinal arterioles secondary to a variety of stimuli.…”

“…Only few compounds have been identified with a constrictive effect on retinal arterioles (Bek, 2019). The constrictive effect of endothelin‐1 is prominent, but the effect is less suitable for vascular physiological experiments due to the risk of tachyphylaxis that leads to irreversible contraction (Torring et al, 2014).…”

Frontiers in diabetic retinal disease

“…Future studies of the mechanisms by which diabetes disturbs the neurovascular unit may yield indices that could serve as physiologic endpoints for clinical studies with short-term durations by which to test potential therapies. 52 …”