Alcohol linked to enhanced angiogenesis in rat model of choroidal neovascularization

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world in people aged over 55. Exudative (i.e. wet-type) AMD is characterized by the development of new vessels within the choroid of the eye (i.e. choroidal neovascularization; CNV) [1]. This neovasculature penetrates Bruch's membrane and grows beneath the retinal pigment epithelium and neurosensory retina [2][3][4][5][6][7]. Many different growth factors have been implicated in the development of choroidal angiogenesis [8][9][10][11][12][13][14][15][16][17][18]; including vascular endothelial growth factor (VEGF) [9,19,20] One of the pathologic complications of exudative (i.e. wet-type) age-related macular degeneration (AMD) is choroidal neovascularization (CNV). The aim of this study was to investigate whether chronic and heavy alcohol consumption influenced the development of CNV in a rat model. The oxidative metabolism of alcohol is minimal or absent in the eye, so that ethanol is metabolized via a nonoxidative pathway to form fatty acid ethyl esters (FAEE). Fatty acid ethyl ester synthase (FAEES) was purified from the choroid of Brown Norway (BN) rats. The purified protein was 60 kDa in size and the antibody raised against this protein showed a single band on western blot. BN rats on a regular diet were fed alcohol for 10 weeks. Control rats were fed water with a regular diet and pair-fed control rats were fed regular diet, water and glucose. We found that FAEES activity was increased 4.0-fold in the choroid of alcohol-treated rats compared with controls. The amount of ethyl esters produced in the choroid of 10 week alcohol-fed rats was 7.4-fold more than rats fed alcohol for 1 week. The increased accumulation of ethyl esters was associated with a 3.0-fold increased expression of cyclin E and cyclin E ⁄ CDK2; however, the level of the cyclin kinase inhibitor, p27Kip, did not change. The increased accumulation of ethyl esters was also associated with 3.0-fold decreased expression of APN in the choroid. We also found that the size of CNV increased by 28% in alcohol-fed rats. Thus, our study showed that chronic, heavy alcohol intake was associated with both an increased accumulation of ethyl esters in the choroid and an exacerbation of the CNV induced by laser treatment. These results may provide insight into the link between heavy alcohol consumption and exudative AMD.Abbreviations AMD, age-related macular degeneration; APN, adiponectin; BN rat, brown Norway rat; CDK2, cyclin E-dependent kinase 2; CNV, choroidal neovascularization; FAEE, fatty acid ethyl ester; FAEES, fatty acid ethyl ester synthase; PEDF, pigment epithelium-derived factor; RPE, retinal pigment epithelium; VEGF, vascular endothelial growth factor.

CD59, a Complement Regulatory Protein, Controls Choroidal Neovascularization in a Mouse Model of Wet-Type Age-Related Macular Degeneration

“…Choroidal angiogenesis (CNV) causing the wet-type AMD is the leading cause of irreversible visual loss in individuals over age 55 (1)(2)(3)(4)(5)(6)(7)(8)(9). We have recently shown that the formation of MAC, as a result of complement activation via the alternative pathway, is essential for the development of laser-induced CNV in mice (6,9).…”

“…Although the nonexudative (dry) form of AMD is more prevalent, catastrophic vision loss is more frequently associated with the exudative (wet) form, specifically from the complication of neovascularization of the choroid (1)(2)(3)(4)(5)(6)(7)(8)(9). Several risk factors have been implicated in the pathogenesis of new choroidal vessel formation (choroidal neovascularization; CNV) in exudative AMD (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

Recombinant Membrane-targeted Form of CD59 Inhibits the Growth of Choroidal Neovascular Complex in Mice

“…Evidence from both human and animal studies supports a key role for complement activation in the development of CNV (7)(8)(9)(10)(11). We demonstrated that membrane attack complex (MAC) formation via the alternative pathway activation is important for the release of angiogenic growth factors that are critical for the induction of CNV in mouse model (9).…”

“…Induction of CNV, Administration of rCD59-APT542 and rsCD59a-Fc-CNV was induced by laser photocoagulation in C57BL/6 mice with an argon laser (50-m spot size, 0.05 s duration, 260 milliwatt) as previously described by us (7)(8)(9). Three laser spots were placed in each eye close to the optic nerve.…”

“…Laser-induced mouse model of CNV in which Bruch's membrane (BM) is disrupted by laser photocoagulation is well established and is used by an increasing number of investigators (4 -7). Over the last ten years, we have noted that rodent model of laser-induced CNV has provided valuable information and contributed significantly to our understanding of the underlying mechanisms involved in the pathogenesis of new vessel growth from the choroid (7)(8)(9)(10).…”