Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology

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Science  25 Aug 2017:
Vol. 357, Issue 6353, eaal2379
DOI: 10.1126/science.aal2379

Dynamic vascular surfaces

Blood vessels have long been considered as passive conduits for blood and circulating cells that, at best, respond to exogenous cytokines. However, recent work has shown that blood vessels serve as a highly dynamic interface between the circulation and tissues. Augustin et al. review molecular mechanisms of vascular development and function in different organs. Differentiated endothelial cells develop as a sort of cobblestone monolayer to form one of the largest surfaces within the body. Vascular control of the tissue microenvironment is vital, not only for normal tissue development and homeostasis, but also for disease states ranging from inflammation to cancer.

Science, this issue p. eaal2379

Structured Abstract


Each organ in the human body has its own capillary bed to carry out its distinctive and versatile functions in response to dynamically changing systemic and local needs. Common and specific functions of the microvasculature in different organs are executed by organ-specifically differentiated endothelial cells (ECs). The morphological differentiation of ECs into barrier-forming continuous ECs, fenestrated ECs, and sinusoidal ECs has long been recognized. Nevertheless, the functional properties and underlying molecular mechanisms of organotypic vasculatures have only been uncovered recently.


This Review covers recent advances in the biology of organotypically differentiated microvascular beds. It describes the key features of continuous, discontinuous, and sinusoidal ECs, as well as the more specialized ECs of Schlemm’s canal and high endothelial venules. Major transcriptional pathways of EC specification and differentiation are outlined, including GATA4 as a key transcription factor of sinusoidal EC differentiation. The molecular shear stress–sensing machinery—which transduces blood flow–mediated biophysical forces that are essential to maintain the quiescent, differentiated EC phenotype—is delineated.

In terms of function, this Review also discusses discoveries in different organs, including liver, lung, and bone, that have identified organotypically differentiated ECs as a source of paracrine (“angiocrine”)–acting cytokines, through which they exert active gatekeeper roles on their microenvironment. ECs thereby control organ development, homeostasis, and tissue regeneration.

On the basis of these general principles of organotypic vascular differentiation and function, this Review comprehensively covers recent landmark discoveries pertaining to the organotypically specialized (micro)vasculature in different organs. Focusing on the molecular structure-function analysis of organotypically differentiated (micro)vasculatures, it specifically highlights the properties of blood vessels in the brain, eyes, heart, lungs, liver, kidneys, bones, adipose tissue, and endocrine glands. Emphasis is given to the contribution of organotypically differentiated vasculatures to both physiological organ function and disease.


Research into the mechanisms of organotypic vascular differentiation and function has emerged in recent years as a new branch of vascular biology, with major implications for our understanding of physiological and pathophysiological organ function. Ongoing research is aimed at deciphering, in much higher resolu­tion (all the way to the single-cell level), the molecular microarchitecture of organotypic vasculatures, understanding the multicellular cross-talk through which organo­typic vasculatures control their microenvironment, dissecting niche functions of organotypic vasculatures with respect to stem cells and their progeny, and unraveling the fate maps of different or­ganotypic vasculatures in health and disease. Future research will not only focus on decipher­ing the molecular mechanisms and functional consequences of organotypic vascular differentia­­tion, but will also aim to translate such knowledge for the develop­ment of novel organ- and vessel bed–specific angiotargeted therapies for multiple diseases that have hitherto been intractable.

Organotypically differentiated vasculatures take center stage in vascular biology research.

Blood vessels in the body (clockwise from top left, vessels in the brain, retina, heart, adrenal gland, bone, and liver) come in different morphologies and have distinct organotypic characteristics that enable them to execute vessel bed–specific functions. They thereby act as gatekeepers of their microenvironments to actively control organ function.


Blood vessels form one of the body’s largest surfaces, serving as a critical interface between the circulation and the different organ environments. They thereby exert gatekeeper functions on tissue homeostasis and adaptation to pathologic challenge. Vascular control of the tissue microenvironment is indispensable in development, hemostasis, inflammation, and metabolism, as well as in cancer and metastasis. This multitude of vascular functions is mediated by organ-specifically differentiated endothelial cells (ECs), whose cellular and molecular heterogeneity has long been recognized. Yet distinct organotypic functional attributes and the molecular mechanisms controlling EC differentiation and vascular bed–specific functions have only become known in recent years. Considering the involvement of vascular dysfunction in numerous chronic and life-threatening diseases, a better molecular understanding of organotypic vasculatures may pave the way toward novel angiotargeted treatments to cure hitherto intractable diseases. This Review summarizes recent progress in the understanding of organotypic vascular differentiation and function.

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