Cell and Tissue Research

, Volume 354, Issue 3, pp 647–669 | Cite as

Innovations in studying in vivo cell behavior and pharmacology in complex tissues – microvascular endothelial cells in the spotlight

  • Elise Langenkamp
  • Jan A. A. M. Kamps
  • Michal Mrug
  • Elisabeth Verpoorte
  • Yilmaz Niyaz
  • Peter Horvatovich
  • Rainer Bischoff
  • Harry Struijker-Boudier
  • Grietje Molema


Many studies on the molecular control underlying normal cell behavior and cellular responses to disease stimuli and pharmacological intervention are conducted in single-cell culture systems, while the read-out of cellular engagement in disease and responsiveness to drugs in vivo is often based on overall tissue responses. As the majority of drugs under development aim to specifically interact with molecular targets in subsets of cells in complex tissues, this approach poses a major experimental discrepancy that prevents successful development of new therapeutics. In this review, we address the shortcomings of the use of artificial (single) cell systems and of whole tissue analyses in creating a better understanding of cell engagement in disease and of the true effects of drugs. We focus on microvascular endothelial cells that actively engage in a wide range of physiological and pathological processes. We propose a new strategy in which in vivo molecular control of cells is studied directly in the diseased endothelium instead of at a (far) distance from the site where drugs have to act, thereby accounting for tissue-controlled cell responses. The strategy uses laser microdissection-based enrichment of microvascular endothelium which, when combined with transcriptome and (phospho)proteome analyses, provides a factual view on their status in their complex microenvironment. Combining this with miniaturized sample handling using microfluidic devices enables handling the minute sample input that results from this strategy. The multidisciplinary approach proposed will enable compartmentalized analysis of cell behavior and drug effects in complex tissue to become widely implemented in daily biomedical research and drug development practice.


(Endothelial) cell behavior Pharmacology In vivo Laser microdissection Omics technology 



Angiotensin converting enzyme


Activin receptor-like Kinase


B-cell lymphoma 2-associated death promoter


Blood–brain barrier


B-cell lymphoma 2




Extracellular matrix


Extracellular signal-regulated kinase


Fibroblast growth factor


Fourier transform mass spectrometry


Hypoxia-inducible factor


High performance liquid chromatography


Intercellular adhesion molecule




Low-density array


Lactase dehydrogenase


Leukocyte function antigen


Long non-coding RNA


Lab on a chip




Matrix-assisted laser desorption/ionization-time of flight (mass spectometry)


Mitogen activated protein kinase


Nuclear factor κ-B


Next generation sequencing


Nitric oxide synthase


Polyacrylamide gel electrophoresis


Platelet-derived growth factor


Phosphoinositide 3-kinase


Protein kinase B


Protein kinase C


Plasmalemma vesicle-associated protein-1


Renal cell carcinoma


Reverse transcriptase-polymerase chain reaction


Surface-enhanced laser desorption/ionization-time of flight (mass spectometry)


Single reaction monitoring


Transforming growth factor


Tumor necrosis factor (receptor)


Tissue-type plasminogen activator


Urokinase-type plasminogen activator


Vascular cell adhesion molecule


Vascular endothelial cadherin


Vascular endothelial growth factor (receptor)


Vascular endothelial protein tyrosine phosphatase


Very late antigen


Vesiculo-vacuolar organelle


Zonal occludens



We are indebted to Dr. Geny M.M. Groothuis for fruitful discussion on species difference and drug metabolism. Research by G.M. and M.M. has in part been funded by the Genzyme Renal Innovations Program.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elise Langenkamp
    • 1
    • 8
  • Jan A. A. M. Kamps
    • 1
  • Michal Mrug
    • 2
    • 3
  • Elisabeth Verpoorte
    • 4
  • Yilmaz Niyaz
    • 5
  • Peter Horvatovich
    • 6
  • Rainer Bischoff
    • 6
  • Harry Struijker-Boudier
    • 7
  • Grietje Molema
    • 1
    • 9
  1. 1.University Medical Center Groningen, Department of Pathology and Medical Biology, Medical Biology sectionUniversity of GroningenGroningenThe Netherlands
  2. 2.Division of Nephrology, Department of Medicine, Nephrology Research and Training CenterUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Department of Veterans Affairs Medical CenterBirminghamUSA
  4. 4.Groningen Research Institute of Pharmacy, Pharmaceutical AnalysisUniversity of GroningenGroningenThe Netherlands
  5. 5.Carl Zeiss Microscopy GmbHJenaGermany
  6. 6.Groningen Research Institute of Pharmacy, Analytical BiochemistryUniversity of GroningenGroningenThe Netherlands
  7. 7.Department of Pharmacology and ToxicologyMaastricht UniversityMaastrichtThe Netherlands
  8. 8.Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
  9. 9.University Medical Center GroningenGroningenThe Netherlands

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