Angiogenesis and Vascular Diseases

Angiogenesis or blood vessel growth from existing blood vessels, is a normal part of retinal blood vessel development. However, in a host of diseases, blood vessels may grow inappropriately and not properly develop leading to disease pathology. For example, in diabetes, blood vessels may grow into the vitreous and pull the retina  away from its proper position and lead to blindness. This pathological vessel growth is called neovascularization and contributes to a host of blinding eye diseases such as diabetes and age related macular degeneration or AMD. Our laboratory has identified a novel role for a tight junction protein occludin in regulation of neovascularization. This finding provides intriguing insight into the the mechanism of action of factors such as vascular endothelial growth factor that contributes to both blood vessel permeability and neovascularization. Our current studies are focused on understanding how the tight junction protein occludin contributes such a critical role in regulating neovascularization and how we can promote normal vessel growth with proper barrier formation.

Retinal vascular permeability leads to macular edema and contributes to vision loss in a host of eye diseases, including retinal vessel occlusions, uveitis, retinopathy of prematurity, and diabetic retinopathy, the leading cause of vision loss of working age adults. Our laboratory has the long-term goal of contributing to the development of novel treatments that target retinal vascular dysfunction to prevent or reverse loss of vision. 

Growth factors such as vascular endothelial growth factor (VEGF) and inflammatory cytokines such as tumor necrosis factor α (TNF) contribute to retinal vascular permeability in diabetic retinopathy as well as a host of other eye diseases. Previous studies in our laboratory have revealed that VEGF alters the tight junction complex leading to increased retinal endothelial permeability, an effect that is characteristic of diabetic retinopathy. These studies have identified specific modifications to proteins in the tight junction that appear to regulate the way the blood vessels are sealed, preventing leakage or increasing permeability, allowing fluid and blood borne material to enter the retina.

Research into these tight junction proteins yielded an unexpected result. Modification to one the tight junction proteins, occludin, not only affected the blood vessel permeability but also contributes to the control of cell proliferation. This finding is significant since vascular endothelial growth factor promotes blood vessel growth or angiogenesis, which is also highly associated with blindness in a host of retinal eye diseases.  Current studies focus on understanding the molecular mechanisms by which the tight junctions contribute to control of vascular permeability and blood vessel growth and identifying ways to block or reverse vascular dysfunction in retinal eye disease.

Abnormal retinal and choroidal vasculature, including vascular permeability and neovascularization, play a critical role in the leading causes of blindness, including macular degeneration, diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity.  While aspects of this pathway have been studied in animal models through immunohistochemistry, limited information is available about what it taking place in vivo in real time in patients in diseased states. The Paulus Advanced Eye Imaging and Laser Laboratory focuses on developing novel molecular imaging methods to probe the cellular and molecular changes taking place in real-time to better characterize and understand the molecular changes, particularly on the process of neovascularization and the role of avb3 and other integrins. We seek to draw parallels between the neovascularization that occurs with cancer and choroidal and retinal neovascularization to develop novel therapies. We use numerous primarily optical and ultrasonic imaging modalities (fluorescence, optical coherence tomography, photoacoustic microscopy, ultrasonography) coupled with targeted multimodal molecular probes (organic nanoparticles, graphene, lipids, gold nanorods, gold nanostars, and microbubbles) to achieve this. This interdisciplinary work includes close collaborations with biomedical engineering, radiology, chemical engineering, chemistry, and materials science. Our group also works on developing novel laser therapies for selectively targeting angiogenesis through the use of ultrafast laser technology in the nanosecond pulse duration concurrently with ultrasound, a novel technique that he and his collaborators have patented termed Photo-mediated Ultrasound Therapy (PUT).

Grant Support

• 4K12EY022299, National Institutes of Health, National Eye Institute
  PI: Thomas Gardner
  05/01/2016 – 04/30/2018
  Real-time In Vivo Visualization of the Molecular Processes in Choroidal Neovascularization
  Role: Scholar
• Fight for Sight – International Retinal Research Foundation FFSGIA16002
  PI: Yannis M. Paulus
  07/01/2016 – 12/31/2017
  Realtime In Vivo Visualization of the Molecular Processes in Retinal and Choroidal Neovascularization
  Role: PI
• Alliance for Vision Research
  PI: Yannis M. Paulus
  03/01/2017 – 02/28/2018
  Photo-mediated Ultrasound Therapy as a Novel Adjunct Therapy for Macular Degeneration
  Role: PI