Andrius Kazlauskas

Andrius Kazlauskas received his BS and PhD degrees in chemistry from Cleveland State University.  His graduate studies focused on signal transduction.  This field involves studying the intracellular biochemical reactions that are induced by growth factors and that then go on to direct cellular responses such as proliferation.  He continued in this area of basic research at the Fred Hutchinson Cancer Research Center in Seattle and then in his own research lab at the National Jewish Center for Immunology and Respiratory Medicine in Denver. He came to the Schepens Eye Research Institute in 1996 to apply the approaches that he used in basic research to blinding eye diseases.  In addition to the blood vessel-regression projects described below, Dr. Kazlauskas is investigating the involvement of growth factors in proliferative vitreoretinopathy. He is currently a Senior Scientist at the Schepens and an Associate Professor in the Department of Ophthalmology at Harvard Medical School. He is funded by grants from the NIH.

What is angiogenesis or abnormal blood vessel growth?

First, angiogenesis is the end result of an elegantly orchestrated sequence of distinct events. (See the Figure.)  Stable, quiescent blood vessels undergo destabilization, and this transition is associated with a loss of the cells (called pericytes) that are normally attached to the outside of blood vessels.  (The vessels themselves are composed of endothelial cells.) Degradation of the surrounding medium (called the extracellular matrix, ECM) enables some of the endothelial cells to migrate out of the vessel.  This process, together with proliferation of endothelial cells and recruitment of circulating endothelial-cell precursors, generates the new vessel.  In the final phase of the angiogenesis program, the new vessels undergo stabilization.  This concludes the angiogenic process of generating new, quiescent blood vessels from existing ones. When this process is properly regulated, as in development and during wound healing, the new vessels are normal, and can carry blood without leaking.
The angiogenic program.  The first step of the angiogenic program is a poorly understood process by which stable blood vessels become de-stabilized.  This step is associated with the loss of pericytes.  The cells of the destabilized vessel migrate into the recently degraded extracellular matrix.  Step 3 is proliferation of cell, whereas the fourth step is the stabilization of the new vessel.

The second important point regarding angiogenesis is that unregulated, abnormal angiogenesis is a major component of two common, blinding eye diseases -- proliferative diabetic retinopathy and the “wet” form of age-related macular degeneration.  New vessels form where they should not be -- in the vitreous or in the choroid -- and fail to mature and become functional.  The new vessels are pathological, and they leak. These abnormal vessels and the fluid that leaks from them often rob an individual of his or her vision.  Understanding what controls the angiogenic program can provide the conceptual foundation for next-generation therapies to manage and prevent these devastating eye diseases.
 
Basic research has revealed that pathological angiogenesis is, at least in part, due to an increase in pro-angiogenic growth factors (such as vascular endothelial growth factor, VEGF) that instruct the endothelial cells to engage the angiogenic program inappropriately.  Consequently, there has been a huge effort to design therapies that interfere with VEGF, and the initial fruits of these labors include Macugen and Lucentis.
 
In light of the fact that patients typically come to their ophthalmologist after pathological blood vessels have developed, therapies designed to induce vessel regression should become the first step in treating such patients.  Consequently, instead of investigating what promotes the formation of blood vessels, we have focused on the signaling pathways responsible for regression of blood vessels.
 
There were three known mechanisms by which blood vessels regress:  Immature vessels, such as those found in tumors and certain pathological ocular beds, are dependent on a continual supply of pro-angiogenic growth factors.  Thus, in some cases, blocking the action of growth factors such as VEGF is sufficient to induce regression, and this explains why Macugen and Lucentis induce at least transient regression in some patients.  However, in other cases, withdrawing the pro-angiogenic growth factors is insufficient to induce regression;  regression factors such as angiopoetin-2 are required to complete the job.  Finally, certain vessel beds regress in response to the arrival of specialized immune system cells called macrophages.  Taken together, these studies demonstrate that regression of blood vessels does not proceed by a uniform mechanism, and suggest that regression therapy will need to be tailored to match the vessels that are being targeted.
 
We recently discovered an additional vessel-regression pathway.  Endothelial cells (the cells the make up the blood vessels) are hard-wired with an intrinsic regression program.  They naturally express the components of a signaling pathway that instructs them to regress.  Furthermore, when the cells of the vessel are stimulated in a way that engages this signaling pathway, the vessels disorganize and the cells undergo programmed cell death.
 
We are pursuing this discovery in the following ways:  First, because our discoveries were made using simple cell-culture (in vitro) model systems, we are testing whether the intrinsic regression pathway regulates the regression of blood vessels in a whole-animal (in vivo) setting.  Second, we are learning how to manipulate the regression pathway, that is, how to induce or suppress it.  Finally, we are testing if manipulating the intrinsic regression pathway is a therapeutic option for controlling the vascularity of various blood-vessel beds within the eye.