En Español | Plain Text Version | Skip Navigation

You are here:  Home > Find People > Groups at NINDS > Stroke Progress Review Group

Neurovascular Protective Mechanisms

Skip secondary menu

Session Chairs

  • Pak H. Chan
  • Gloria Z. Feuerstein
Contact: Michael A. Moskowitz

Start time 10:30 a.m.
End time 1:00 p.m.

Participants

Mark P. Goldberg
Neil Granger
John M. Hallenbeck
Chung Y. Hsu
Patricia D. Hurn
Gary A. Rosenberg
David M. Stern
Raymond Swanson

Agenda

Theme I: Cerebrovascular Endothelium

Background- state of the art knowledge:

  • The endothelium of brain vessels (including capillaries) is viewed as an active participant cell in securing flow, nutrition, seclusion and immune surveillance of normal brain tissue.
  • The endothelium maintains its function via 'on line' interactions with cellular elements of abluminal (astrocytes, pericytes) and luminal (leukocytes, platelets, RBC) location. In addition, the endothelium interacts with neuronal, humoral and matrix derived factors as well as autocrine and paracrine mechanisms that secure in the physiological state the following phenotype:
  • Secure and regulate adequate blood flow to brain tissue.
  • Anti-adhesive
  • Anti-inflammatory
  • Anti-thrombotic
  • Establish Blood Brain Barrier (BBB)
  • The endothelium may revert under certain conditions to a cellular phenotype incompatible with maintenance of its critical role in blood flow and BBB function. Such conditions were suggested:
  • Inflammatory mediators (e.g., cytokines, chemokines, lipid mediators)
  • Coagulation factors and platelets
  • Inadequate shear rates and flow patterns
  • Failure to maintain autocrine (nitric oxide) and paracrine protective factors
  • Redox imbalances (oxidative stress)
  • Aberrant matrix signaling and support
  • Neurohormonal factors (gender hormone, vasoactive Neurohormonal factors)
  • The endothelium under pathophysiological conditions (vide supra) may assume pro-thrombotic, pro-inflammatory phenotype which leads to neurovascular damage. Furthermore, under such conditions, apoptosis and other degenerative changes in the endothelium lead to loss of the vascular unit and ultimately, brain injury.

Issues and scientific/technological gaps:

  • While a large database of information regarding the stimuli and mediators that effect endothelium phenotype are known, limited or no data exists on the signaling pathways that govern endothelial cell survival or death. The cytosolic and nuclear pathways that translate such external signals are poorly understood.
  • While plethora of work outlines blood borne, Neurohormonal, oxidative stress and inflammatory/immune factors in endothelial cells phenotype 'switch', the role of matrix proteins and endothelial-matrix adhesion molecules in regulating endothelium phenotype is unknown.
  • The role of glia cells and neurons derived factors in regulation of endothelium and blood brain barrier (BBB) is unknown.
  • Survival factor and mechanisms that lead to tolerance to endothelium injury and death have not been elucidated.
  • Technology that allows to investigate the integrated function of the brain microvessels in the context of all relevant cells (glia, pericytes, neurons) and matrix proteins has not been developed as yet. Likewise, it is currently impossible to study brain microvessels functions in vivo or in humans (normal, individuals at risk for stroke and stroke patients).
  • Strategies for endothelium cell therapy or replacement (stem cells) have not been developed.

Recommendations:

  • Identify the fundamental molecular mechanisms and the genetic underpinning of endothelium survival and death pathways. Identify 'master switches' that enable genomic formatting of endothelial cells to perform physiological function and over-ride pathological events.
  • Establish research and technology that enable to determine unambiguously the role of the endothelium and BBB unit as risk factor in stroke, ischemic brain injury and healing/regeneration.
  • Develop technologies that allow direct investigation of integrated brain vessel units (endothelium, glia and matrix) in vivo and humans
  • Apply genomic, proteomics and genetic strategies to investigate all the components of the brain vessel unit in stroke and other neurovascular degenerative diseases.
  • Establish research on endothelium cell therapy in view of need for re-construction of brain vascular system in stroke and other neurodegenerative diseases.

Theme II: Glia cells role in neurovascular function

Background- state of the art knowledge:

  • Astrocytes are an integrated brain cell of direct access to the microvascular unit where its processes govern endothelium and BBB function
  • Astrocytes and microglia release factors that may govern endothelial cells growth and survival as well injury and death.
  • Microglia and astrocyte activation may provide for an in situ inflammatory reaction that may amplify and modulate external immune/inflammatory reactions, BBB function and repair processes
  • Astrocyte and microglia may produce and release toxic proteins such as Amyloid beta that induced angiopathic conditions that bear significantly on neurodegenerative disorders and serve as risk factors for ischemic brain damage (CADASIL).

Issues and scientific/technological gaps:

  • There is a clear paucity of knowledge on the cell biology, biochemistry and molecular biology of glia cells activation, proliferation and mediators release. In particular, growth and survival promoting factors need to be investigated.
  • The intercellular connections and pathways that govern glia cells regulation of the BBB are poorly understood.
  • The scope of cytotoxic and angiopathic mediators that are derived from astrocytes and other glia cells interacting with endothelium is deficient.
  • The role of astrocytes and microglia in matrix (especially endothelium basement membrane biology) matrix metalloproteases (MMPs) and matrix-glia adhesion and matrix-endothelium adhesion molecule regulation is unclear.
  • The role of astrocyte and microglia in repair and reconstruction processes in ischemic brain injury is unclear.
  • Glia cells genomics is still unavailable. Stimuli, signaling pathways and 'molecular switches' mechanism that secure physiological phenotype of astrocyte and microglia need to be established.

Recommendations:

  • Support research that decisively establish whether or not glia cells play a key role as risk factors in stroke and neurovascular degenerative conditions.
  • Develop in vitro and in vivo models that yield clear insights on the interaction of glia cells with the endothelium and its basement membrane (matrix milieu).

Theme III: Matrix proteins and its regulatory

Background- state of the art knowledge:

  • The extra-cellular matrix (ECM) is a critical element in organ development, remodeling, angiogenesis, cell survival and death.
  • Physiological matrix milieu is dependent on several cellular contributors (astrocytes, microglia, endothelium) and regulatory enzymes including the matrix metalloproteases (MMPs) and the ADAM family of proteases.
  • The endothelium basement membrane is a specialized matrix milieu that structurally and functionally supports the vascular unit function.
  • Active, regulated and genomically imprinted processes secure 'ever green' matrix milieu provides signaling input to both the endothelium and glia cells that compose the BBB
  • Pathological changes in matrix compositions and MMPs (gelatinases) disrupt endothelium function as well as glia cells. Such aberration lead to disruption of the BBB.
  • The ECM may play a role in initiation of stroke, vasculopathies conditions and BBB malfunctions. The role of specific MMPs in this respect as elucidated by pharmacological investigational tools and genetic models carry the promise for preventive and therapeutic opportunities for stroke and neurodegenerative disorders in the near future

Issues and scientific/technological gaps:

  • A vast number of novel MMPs and ADAM proteases have been discovered over the past few years yet little is known on their role in brain matrix and BBB function. There is an urgent need to identify the relevant and important MMPs and ADAMs that could be risk factors for stroke and other neurodegenerative disorders.
  • The specific associations of matrix proteins with cell (glia, endothelium) adhesion molecules and the signaling pathways that regulate vascular cell biology are poorly understood.
  • Pharmacological tools that provide for selective and potent inhibition of specific MMPs and ADAMs need to be developed to allow better understanding of their function in normal and disease condition. Likewise, genetic models need to be developed to answer these issues.
  • Genetic information on matrix proteins and MMPs/ADAMs need to be generated to gain insights on possible polymorphism in matrix and regulating elements as risk factors for stroke.
  • Genomic explorations of the complete set of matrix proteins and the regulatory elements (proteases and protease inhibitors) needs to be completed.
  • The role of the ECM in healing processes and angiogenesis in brain disorders is largely unknown.

Recommendations:

  • Initiate large scale, genomically and genetically based search to identify the complete set of ECM proteins and their regulatory enzymatic machinery in the human brain.
  • Investigate the trascriptional, translational and regulatory events that govern balanced, physiologically functional matrix milieu
  • Generate genetic registry of polymorphism of ECM and MMPs/ADAMs that serve as risk factors for stroke and vascular degenerative disorders.
  • Establish interdisciplinary collaboration between cancer sciences, immunologists/rheumatologists and other National and international organizations concerned with ECM associated diseases.
  • Develop technology that allows imaging (quantitatively and qualitatively) of human brain and vascular basement membrane matrix proteins in health and diverse disease conditions.

Last updated August 13, 2008