Heterogeneity in responses of microvascular endothelial cel
Posted: Sat Sep 19, 2015 10:32 am
Olga had brought up an interesting concept with Lisa on why the pazonib may of worked on her lung mets but not on a breast tumor
http://www.cureasps.org/forum/viewtopic ... t=15#p8441
Heterogeneity in responses of microvascular endothelial cells during inflamation
Abstract
Each segment of the vascular system has its own function, based on its location in the body. The
endothelial cells lining these vascular segments are an intrinsic part of this segmental variation, and
it is not surprising that throughout the vascular bed they have a highly heterogenic appearance.
This chapter starts with a description of the heterogenic phenotype of endothelial cells in the body
in quiescent conditions. Focus is next on endothelial engagement in inflammatory processes and
how the microvascular endothelial cells in the different organs and within an organ respond to
tumor necrosis factor α, interleukin-1, and lipopolysaccharide as inflammatory stimuli. Studies on
endothelial responsiveness both in vitro in culture systems and in vivo in the intact body are discussed.
From a pharmacological point of view, knowledge of the molecular basis of heterogeneity
in endothelial cell behavior will be critical for successful drug development to counteract endothelial
cell engagement in disease. This chapter therefore concludes with a short overview of technological
advancements that may assist in unveiling the mechanisms responsible. When applied to
address microvascular endothelial heterogeneity, major steps forward in endothelial biomedicine
are anticipated that will assist in defining the right molecular targets for the microvascular segments
involved in the pathology under study.
Concluding remarks
A generic endothelial cell does not exist. Depending on the location in the body,
endothelial cells have their own molecular make up that drives basic behavior, as
well as responses to inciting stimuli. Loss of microenvironment-driven control when
using cultured endothelial cells is a major hurdle in obtaining a detailed picture of
the molecular basis of heterogeneity that drives endothelial performance in vivo.
Application of new technologies may assist in overcoming some of these hurdles, as
may well-designed so-called in vivo-in vitro-in vivo experimental schemes in which
29
Heterogeneity in responses of microvascular endothelial cells during inflammation
in vivo observations are modeled in vitro to obtain a more detailed understanding
of the molecular identity of processes, which are next immediately validated
in the in vivo environment. Although mouse models are a powerful tool to study
endothelial engagement in inflammatory diseases, from a pharmacological and
drug development point of view, knowledge of their role and responses to drug
treatment in patients is crucial. For this we need to identify systemic biomarkers of
activation of the endothelial cells in the specific vascular segments that are involved
in the disease. We should carefully monitor the endothelial compartment in animal
models for genes that engage in disease initiation and/or progress, that are mainly
endothelial cell driven, and that can be monitored in serum by virtue of the fact
that the proteins they encode are shed from the cell membrane. Validation of their
potential as real biomarkers in patients will not be easy, but should be pursued.
Together with our ongoing quest to unravel the molecular and functional meaning
of microvascular endothelial heterogeneity, this will eventually enable us to develop
pharmacologically effective drugs targeted at those endothelial compartments that
engage in disease while bypassing the ones that are not involved.
Acknowledgements
Dr. Joanna M. Kuldo is acknowledged for skillful execution of experiments that
http://www.springer.com/cda/content/doc ... p174060476
http://www.cureasps.org/forum/viewtopic ... t=15#p8441
Heterogeneity in responses of microvascular endothelial cells during inflamation
Abstract
Each segment of the vascular system has its own function, based on its location in the body. The
endothelial cells lining these vascular segments are an intrinsic part of this segmental variation, and
it is not surprising that throughout the vascular bed they have a highly heterogenic appearance.
This chapter starts with a description of the heterogenic phenotype of endothelial cells in the body
in quiescent conditions. Focus is next on endothelial engagement in inflammatory processes and
how the microvascular endothelial cells in the different organs and within an organ respond to
tumor necrosis factor α, interleukin-1, and lipopolysaccharide as inflammatory stimuli. Studies on
endothelial responsiveness both in vitro in culture systems and in vivo in the intact body are discussed.
From a pharmacological point of view, knowledge of the molecular basis of heterogeneity
in endothelial cell behavior will be critical for successful drug development to counteract endothelial
cell engagement in disease. This chapter therefore concludes with a short overview of technological
advancements that may assist in unveiling the mechanisms responsible. When applied to
address microvascular endothelial heterogeneity, major steps forward in endothelial biomedicine
are anticipated that will assist in defining the right molecular targets for the microvascular segments
involved in the pathology under study.
Concluding remarks
A generic endothelial cell does not exist. Depending on the location in the body,
endothelial cells have their own molecular make up that drives basic behavior, as
well as responses to inciting stimuli. Loss of microenvironment-driven control when
using cultured endothelial cells is a major hurdle in obtaining a detailed picture of
the molecular basis of heterogeneity that drives endothelial performance in vivo.
Application of new technologies may assist in overcoming some of these hurdles, as
may well-designed so-called in vivo-in vitro-in vivo experimental schemes in which
29
Heterogeneity in responses of microvascular endothelial cells during inflammation
in vivo observations are modeled in vitro to obtain a more detailed understanding
of the molecular identity of processes, which are next immediately validated
in the in vivo environment. Although mouse models are a powerful tool to study
endothelial engagement in inflammatory diseases, from a pharmacological and
drug development point of view, knowledge of their role and responses to drug
treatment in patients is crucial. For this we need to identify systemic biomarkers of
activation of the endothelial cells in the specific vascular segments that are involved
in the disease. We should carefully monitor the endothelial compartment in animal
models for genes that engage in disease initiation and/or progress, that are mainly
endothelial cell driven, and that can be monitored in serum by virtue of the fact
that the proteins they encode are shed from the cell membrane. Validation of their
potential as real biomarkers in patients will not be easy, but should be pursued.
Together with our ongoing quest to unravel the molecular and functional meaning
of microvascular endothelial heterogeneity, this will eventually enable us to develop
pharmacologically effective drugs targeted at those endothelial compartments that
engage in disease while bypassing the ones that are not involved.
Acknowledgements
Dr. Joanna M. Kuldo is acknowledged for skillful execution of experiments that
http://www.springer.com/cda/content/doc ... p174060476