Photo of Alexander G. Marneros,  MD, PhD

Alexander G. Marneros, MD, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 643-7170

Alexander G. Marneros, MD, PhD

Massachusetts General Hospital

Research Abstract

Abnormal blood vessel growth is an important component in the pathogenesis of various common diseases. Pathological angiogenesis is stimulated by an inflammatory response that involves many different cell types, including proangiogenic macrophages. Our laboratory focuses on the factors and cell types that promote pathologic angiogenesis in development, in the adult and during aging.


Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly. Non-exudative (“dry”) AMD manifests with degeneration of the retinal pigment epithelium (RPE) and sub-RPE deposit formation with progressive age. Neovascular (“wet”) AMD manifests with pathologic neovascularization from the choroid into the retina. Often both forms co-occur, suggesting a common pathomechanism. We have recently shown in a new mouse model of AMD that increased VEGF-A is sufficient to cause both forms of AMD, providing evidence for a unifying pathomechanism in advanced AMD. In this model, proangiogenic macrophages stimulate retinal glia cells to promote choroidal neovascularization. Furthermore, we could show that the NLRP3 inflammasome promotes VEGF-A-induced AMD pathologies, and targeting inflammasome components inhibits these pathologies. Our work focuses on elucidating the mechanisms that regulate molecular pathways and cellular interactions during AMD pathogenesis, with the aim of identifying novel therapeutic approaches for patients with AMD.


Multiple cell types interact in a highly coordinated fashion in response to injury to promote wound healing. Abnormalities in this complex process can result in exuberant wound angiogenesis or scarring. We use in vivo models of wound healing to determine the spatiotemporal contributions of various cell types in this process. In a laser-injury model of choroidal neovascularization, we could show that macrophages become alternatively activated (M2-type) and promote wound angiogenesis, in part by stimulating retinal glia cells to express proangiogenic growth factors. Specific ablation of macrophages inhibits the early wound healing response to injury and blocks wound angiogenesis. Our current research investigates which signaling pathways drive polarization of macrophages to the proangiogenic M2-type in vivo and how this polarization can be inhibited. Overall, we aim to define the contributions of individual inflammatory cell populations to wound healing and neovascularization.


Wound healing and wound angiogenesis occur in response to injury. However, congenital wounds are observed in various genetic syndromes as a manifestation of a skin morphogenesis defect during embryonic development. Identifying the genetic basis for these conditions and syndromes promises to identify novel genes and pathways that are critical for proper skin formation and whose impairment results in wounds. A prototypical congenital skin disease that manifests with a wound present at birth is aplasia cutis congenita (ACC). Using a combination of genome-wide linkage analysis and exome sequencing we recently identified the causative mutation for ACC. We found that the ribosomal GTPase BMS1 is mutated in ACC, which results in a maturation defect of the small ribosomal subunit and leads to a nucleolar stress response with a p21-mediated G1/S phase transition delay and a reduced cell proliferation rate. Global proteomic and transcriptional analyses revealed a central role of p21 activation for the ACC phenotype.

Our laboratory investigates how a mutation in a ubiquitous ribosomal protein leads to localized skin defects without affecting other organ systems. We seek to obtain a comprehensive understanding of the disease mechanisms of congenital wound healing disorders.


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  • Strittmatter K, Pomeroy H, Marneros AG. Targeting Platelet-Derived Growth Factor Receptor β(+) Scaffold Formation Inhibits Choroidal Neovascularization. Am J Pathol 2016; 186:1890-9. PubMed
  • Marneros AG. Increased VEGF-A promotes multiple distinct aging diseases of the eye through shared pathomechanisms. EMBO Mol Med 2016; 8:208-31. PubMed
  • He L, Marioutina M, Dunaief JL, Marneros AG. Age- and gene-dosage-dependent cre-induced abnormalities in the retinal pigment epithelium. Am J Pathol 2014; 184:1660-7. PubMed
  • Ablonczy Z, Dahrouj M, Marneros AG. Progressive dysfunction of the retinal pigment epithelium and retina due to increased VEGF-A levels. FASEB J. 2014. PubMed
  • He L, Marneros AG. Doxycycline inhibits polarization of macrophages to the proangiogenic M2-type and subsequent neovascularization. J Biol Chem 2014; 289:8019-28. PubMed
  • Marneros AG. NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration. Cell Rep 2013; 4:945-58. PubMed
  • He L, Marneros AG. Macrophages are essential for the early wound healing response and the formation of a fibrovascular scar. Am J Pathol 2013. PubMed
  • Marneros AG. BMS1 is mutated in aplasia cutis congenita. PLoS Genet. 2013; 9:e1003573. PubMed
  • Marneros AG, Beck AE, Turner EH, McMillin MJ, Edwards MJ, Field M, de Macena Sobreira NL, Perez AB, Fortes JA, Lampe AK, Giovannucci Uzielli ML, Gordon CT, Plessis G, Le Merrer M, Amiel J, Reichenberger E, Shively KM, Cerrato F, Labow BI, Tabor HK, Smith JD, Shendure J, Nickerson DA, Bamshad MJ, . Mutations in KCTD1 cause scalp-ear-nipple syndrome. Am J Hum Genet 2013; 92:621-6. PubMed
  • Makinodan E, Marneros AG. Protein kinase A activation inhibits oncogenic Sonic hedgehog signalling and suppresses basal cell carcinoma of the skin. Exp Dermatol 2012; 21:847-52. PubMed
  • Marneros AG, Grossman ME, Silvers DN, Husain S, Nuovo GJ, MacGregor-Cortelli B, Neylon E, Patterson M, O'Connor OA, Zain JM. Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions. Blood 2009; 113:6338-41. PubMed
  • Marneros AG. Tumor angiogenesis in melanoma. Hematol Oncol Clin North Am 2009; 23:431-46, vii-viii. PubMed
  • Marneros AG, Blanco F, Husain S, Silvers DN, Grossman ME. Classification of cutaneous intravascular breast cancer metastases based on immunolabeling for blood and lymph vessels. J Am Acad Dermatol 2009; 60:633-8. PubMed
  • Marneros AG, She H, Zambarakji H, Hashizume H, Connolly EJ, Kim I, Gragoudas ES, Miller JW, Olsen BR. Endogenous endostatin inhibits choroidal neovascularization. FASEB J 2007; 21:3809-18. PubMed
  • Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, Olsen BR. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 2005; 167:1451-9. PubMed
  • Marneros AG, Olsen BR. Physiological role of collagen XVIII and endostatin. FASEB J 2005; 19:716-28. PubMed
  • Marneros AG, Krieg T. Keloids--clinical diagnosis, pathogenesis, and treatment options. J Dtsch Dermatol Ges 2005; 2:905-13. PubMed
  • Marneros AG, Norris JE, Watanabe S, Reichenberger E, Olsen BR. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol 2004; 122:1126-32. PubMed
  • Marneros AG, Keene DR, Hansen U, Fukai N, Moulton K, Goletz PL, Moiseyev G, Pawlyk BS, Halfter W, Dong S, Shibata M, Li T, Crouch RK, Bruckner P, Olsen BR. Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function. EMBO J 2004; 23:89-99. PubMed
  • Marneros AG, Olsen BR. Age-dependent iris abnormalities in collagen XVIII/endostatin deficient mice with similarities to human pigment dispersion syndrome. Invest Ophthalmol Vis Sci 2003; 44:2367-72. PubMed
  • Fukai N, Eklund L, Marneros AG, Oh SP, Keene DR, Tamarkin L, Niemelä M, Ilves M, Li E, Pihlajaniemi T, Olsen BR. Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J 2002; 21:1535-44. PubMed