Receptor activity-modifying proteins of adrenomedullin (RAMP2/3): Roles in the pathogenesis of ARDS.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition characterized by widespread inflammation and pulmonary edema. Adrenomedullin (AM), a bioactive peptide with various functions, is expected to be applied in treating ARDS. Its functions are regulated primarily by two receptor activity-modifying proteins, RAMP2 and RAMP3, which bind to the AM receptor calcitonin receptor-like receptor (CLR). However, the roles of RAMP2 and RAMP3 in ARDS remain unclear. We generated a mouse model of ARDS via intratracheal administration of lipopolysaccharide (LPS), and analyzed the pathophysiological significance of RAMP2 and RAMP3. RAMP2 expression declined with LPS administration, whereas RAMP3 expression increased at low doses and decreased at high doses of LPS. After LPS administration, drug-inducible vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-) showed reduced survival, increased lung weight, and had more apoptotic cells in the lungs. DI-E-RAMP2-/- mice exhibited reduced expression of Epac1 (which regulates vascular endothelial cell barrier function), while RAMP3 was upregulated in compensation. In contrast, after LPS administration, RAMP3-/- mice showed no significant changes in survival, lung weight, or lung pathology, although they exhibited significant downregulation of iNOS, TNF-α, and NLRP3 during the later stages of inflammation. Based on transcriptomic analysis, RAMP2 contributed more to the circulation-regulating effects of AM, whereas RAMP3 contributed more to its inflammation-regulating effects. These findings indicate that, while both RAMP2 and RAMP3 participate in ARDS pathogenesis, their functions differ distinctly. Further elucidation of the pathophysiological significance and functional differences between RAMP2 and RAMP3 is critical for the future therapeutic application of AM in ARDS.

Role of Adrenomedullin 2/Intermedin in the Pathogenesis of Neovascular Age-Related Macular Degeneration.

Adrenomedullin 2 (AM2; also known as intermedin) is a member of the adrenomedullin (AM) peptide family. Similarly to AM, AM2 partakes in a variety of physiological activities. AM2 has been reported to exert protective effects on various organ disorders; however, its significance in the eye is unknown. We investigated the role of AM2 in ocular diseases. The receptor system of AM2 was expressed more abundantly in the choroid than in the retina. In an oxygen-induced retinopathy model, physiological and pathologic retinal angiogenesis did not differ between AM2-knockout (AM2-/-) and wild-type mice. In contrast, in laser-induced choroidal neovascularization, a model of neovascular age-related macular degeneration, AM2-/- mice had enlarged and leakier choroidal neovascularization lesions, with exacerbated subretinal fibrosis and macrophage infiltration. Contrary to this, exogenous administration of AM2 ameliorated the laser-induced choroidal neovascularization-associated pathology and suppressed gene expression associated with inflammation, fibrosis, and oxidative stress, including that of VEGF-A, VEGFR-2, CD68, CTGF, and p22-phox. The stimulation of human adult retinal pigment epithelial (ARPE) cell line 19 cells with TGF-ß2 and TNF-α induced epithelial-to-mesenchymal transition (EMT), whereas AM2 expression was also elevated. The induction of EMT was suppressed when the ARPE-19 cells were pretreated with AM2. A transcriptome analysis identified 15 genes, including mesenchyme homeobox 2 (Meox2), whose expression was significantly altered in the AM2-treated group compared with that in the control group. The expression of Meox2, a transcription factor that inhibits inflammation and fibrosis, was enhanced by AM2 treatment and attenuated by endogenous AM2 knockout in the early phase after laser irradiation. The AM2 treatment of endothelial cells inhibited endothelial to mesenchymal transition and NF-κB activation; however, this effect tended to be canceled following Meox2 gene knockdown. These results indicate that AM2 suppresses the neovascular age-related macular degeneration-related pathologies partially via the upregulation of Meox2. Thus, AM2 may be a promising therapeutic target for ocular vascular diseases.

Application of optical coherence tomography angiography to assess systemic severity in patients with hereditary transthyretin amyloidosis.

Hereditary transthyretin amyloidosis is an autosomal dominant form of amyloidosis caused by an abnormality in transthyretin, with various ocular manifestations. Among these, ocular amyloid angiopathy has attracted attention because of its direct link to visual impairment and its correlation with systemic severity. We hypothesized that optical coherence tomography angiographic parameters would be useful biomarkers of amyloidosis systemic severity and investigated their correlation with the systemic severity score. The primary outcome was the correlation between the systemic severity score and choriocapillaris flow deficit percentage. Secondary outcomes were the correlations between the systemic severity score and retinal optical coherence tomography angiographic parameters, including foveal avascular zone size and circularity and superficial/deep/total retinal perfusion and vessel densities. The choroidal and retinal vasculature was quantified in 36 eyes from 36 patients (age, 51.8±12.1 years; disease duration, 13.4±6.2 years). Ten eyes had a history of vitrectomy for vitreous opacity. Choriocapillaris flow deficit percentage was not significantly correlated with the systemic severity score (Spearman's rank correlation: r = 2.96×10-2, p = 0.863). Similarly, foveal avascular zone size and circularity, and superficial/deep/total retinal perfusion and vessel densities were not significantly correlated with the systemic severity score. These results may indicate that optical coherence tomography angiographic parameters are not sufficient to predict amyloidosis severity.

OCULAR ANGIOGRAPHIC FEATURES IN JAPANESE PATIENTS WITH VAL30MET HEREDITARY TRANSTHYRETIN AMYLOIDOSIS.

PURPOSE: To investigate ocular angiographic features of hereditary transthyretin amyloidosis with transthyretin Val30Met mutation (hATTR-V30M) in Japanese patients. METHODS: We retrospectively reviewed 102 eyes of 51 patients with hATTR-V30M who underwent fluorescein angiograms and indocyanine green angiograms between 2012 and 2018. Systemic severity score, fluorescein angiograms, indocyanine green angiograms, and ocular amyloidosis presentations at the final angiograms and subsequent neovascular events were evaluated. Primary outcomes were the frequency of choroidal amyloid angiopathy and retinal amyloid angiopathy (RAA). Secondary outcomes were their correlations to the systemic severity score. RESULTS: Six eyes could not be evaluated by fluorescein angiogram because of vitreous opacity. Of 96 eyes evaluated, RAA was detected in 36 (37.5%). Neovascularization was not detected. Indocyanine green angiogram indicated choroidal amyloid angiopathy in 46/51 patients (90.2%), with distinct patterns-diffuse (n = 6), focal (n = 14), and punctiform (n = 26)-based on late-phase hypercyanescence. Retinal amyloid angiopathy and choroidal amyloid angiopathy grades were associated with systemic severity (ρ = 0.57 and 0.50, respectively; both P < 0.05). At 35.4 ± 28.4 (0-96) months, iris-rubeosis was observed in one eye and vitreous hemorrhage in two. CONCLUSION: Retinal amyloid angiopathy was less common and choroidal amyloid angiopathy was frequent, and their severity correlated with the systemic severity score. The frequencies of RAA and subsequent neovascular events in this study may suggest regional differences in the ocular angiographic features of hATTR-V30M.

Deposits on Retinal Surface Seen on OCT in Ocular Amyloidosis.

PURPOSE: To investigate the tomographic features in patients with hereditary amyloidosis transthyretin (hATTR). DESIGN: Retrospective case series and analysis of B-scan OCT images. PARTICIPANTS: A total of 120 patients (240 eyes) diagnosed with hATTR. METHODS: We performed a retrospective review of the treatment history and retrospective analysis of the OCT images of patients with hATTR. The parameters analyzed were the age at which the last OCT was performed, presence of ocular amyloidosis, history of pars plana vitrectomy (PPV), systemic treatment, and genetic mutations. Two independent evaluators evaluated the OCT images for characteristic needle-shaped pattern deposits on the retinal surface, and a third evaluator resolved any differences in their evaluations. MAIN OUTCOME MEASURES: The frequency of characteristic needle-shaped deposits on the retinal surface seen on OCT. RESULTS: The mean age at the time of the last OCT was 56.5 ± 14.9 years. Ninety-nine patients had gene encoding transthyretin (TTR) with the Val30Met mutation, and 21 patients had other mutations. Of 240 eyes, 128 had signs of ocular amyloidosis. Fifty of 73 eyes (68.5%) with a history of PPV for vitreous opacities exhibited characteristic deposits on OCT. Four of 31 eyes with vitreous opacity but without a history of PPV showed deposits on the retinal surface. No eyes without a history of vitreous opacities revealed the characteristic needle-shaped deposits. CONCLUSIONS: Characteristic needle-shaped deposits on the retinal surface seen on OCT are significant because they are seen in most of the vitrectomized eyes presenting with ocular amyloidosis.