Morphological and functional heterogeneity of endothelial cells: the chicken and the egg problem?
Problem or question being addressed
The anatomical heterogeneity of blood vessels in different organs has been long recognized   . ECs have been increasingly accepted as active players implicated in the regulation of many processes, rather than just a passive monolayer of conduit cells . Vascular heterogeneity is essential in order to achieve such highly specialized functions, and can be displayed as a variety of features [5, 6]. Morphological heterogeneity is the most evident whereby ECs from arteries, veins, and capillaries differ in morphology, size, and orientation with respect to the direction of blood flow . Additionally, the complexity in cellular morphology is different among organs and vascular beds. For example, ECs lining capillaries can be defined as continuous, fenestrated, and sinusoidal or discontinuous; and the distinct morphology of capillaries from different organs is closely related to the heterogeneity in vascular functions. However, whether functional heterogeneity precedes anatomical diversity or, instead, the diversity in morphology of different capillaries is responsible for the function of those organs, remains to be elucidated.
Details of suggested approach
With the aim of understanding if, functional heterogeneity precedes anatomical heterogeneity; the recently developed organ-on-a-chip (OOC) technology could be utilized. Briefly, this technology is designed to mimic organ structures and create conditions for functional connections between cells. Three-dimensional representations of the cellular structures of the organs are created, and together with their natural microenvironments’ microfluidic systems and specific physical conditions, they recapitulate as close as possible the natural biology of the structures of those organs . Already developed OOC models of the liver , heart  or brain  could be coupled with ECs from different origins, such as glomerular, brain or sinusoidal ECs, respectively. As such, changes in morphology of ECs could be studied, as well as possible changes in the functions of the organoids. Therefore, if ECs change their morphology to adapt to the OOC they have been coupled to, it would indicate that function precedes morphology. However, if the functional characteristics of the OOC change before the morphology of the ECs within them, it would suggest the morphology antecedes function.
How it will affect the broader field
This approach will shed some light into the biological/philosophical question of whether function precedes morphology and open potential new avenues into understanding how endothelial cell-cell communication is displayed at a larger, organ level. Therapies targeting ECs have been developed , however, none of them can be used for all tissues/organs. Understanding the uniqueness of ECs in different organs would facilitate the development of more targeted therapies against the vascular endothelium. Additionally, the strategy above-mentioned will interconnect various technical approaches including microfluidics, biophysics and cell biology, which requires the collaboration of multidisciplinary groups. As Darwin once said: “In the long history of humankind (and animal kind, too) those who learned to collaborate and improvise most effectively have prevailed”.
1. Aird, W. C. (2007) Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms, Circ Res. 100, 158-73.
2. Aird, W. C. (2007) Phenotypic heterogeneity of the endothelium: II. Representative vascular beds, Circ Res. 100, 174-90.
3. Aird, W. C. (2012) Endothelial Cell Heterogeneity, Cold Spring Harbor Perspectives in Medicine. 10.1101/cshperspect.a006429.
4. Palade, G. E., Simionescu, M. & Simionescu, N. (1979) Structural aspects of the permeability of the microvascular endothelium., Acta Physiologica Scandinavica Supplementum. 463, 11-32.
5. Li, P. & Ferrara, N. (2022) Vascular heterogeneity: VEGF receptors make blood vessels special, J Exp Med. 219.
6. Augustin, H. G. & Koh, G. Y. (2017) Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology, Science. 357.
7. Bennett, H. S., Luft, J. H. & Hampton, J. C. (1959) Morphological classifications of vertebrate blood capillaries, Am J Physiol. 196, 381-90.
8. Bulboacă AE, Boarescu PM, Melincovici CS, Mihu CM. (2020) Microfluidic endothelium-on-a-chip development, from in vivo to in vitro experimental models. Rom J Morphol Embryol. 61:15-23.
9.Beckwitt CH, Clark AM, Wheeler S, Taylor DL, Stolz DB, Griffith L, Wells A. (2018) Liver 'organ on a chip'. Exp Cell Res. 363:15-25.
10. Zhao Y, Rafatian N, Feric NT, Cox BJ, Aschar-Sobbi R, Wang EY, Aggarwal P, Zhang B, Conant G, Ronaldson-Bouchard K, Pahnke A, Protze S, Lee JH, Davenport Huyer L, Jekic D, Wickeler A, Naguib HE, Keller GM, Vunjak-Novakovic G, Broeckel U, Backx PH, Radisic M. A. (2019) Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling. Cell. 176:913-927.
11. Ahn SI, Sei YJ, Park HJ, Kim J, Ryu Y, Choi JJ, Sung HJ, MacDonald TJ, Levey AI, Kim Y. Microengineered human blood-brain barrier platform for understanding nanoparticle transport mechanisms. (2020) Nat Commun. 11:175.
12. Kiseleva RY, Glassman PM, Greineder CF, Hood ED, Shuvaev VV, Muzykantov VR. Targeting therapeutics to endothelium: are we there yet? (2018) Drug Deliv Transl Res. 8:883-902.