The morphogenesis, homeostasis and regeneration of organs involves complex and interdependent communication between different cell types. We mainly focus on the vertebrate vascular system, in which blood vessels need to integrate precisely into different organ environments and retain plasticity allowing them to adapt to changing local requirements and signals. Work of my laboratory has provided fundamental insight into the molecular regulation of angiogenesis and, in particular, the functional roles of vascular cells in developing, adult and aging organs. Our studies have also contributed to the elucidation of disease processes and have identified the genetic cause of several human syndromes.

Tissue-specific specialization of blood vessels with a focus on bone

Blood vessels form a versatile and adaptable conduit system for the transport of a wide range of different molecules and cells, but increasing evidence supports that vascular cells also critically control organ growth, patterning and regeneration by releasing molecular signals that act on the surrounding tissue. We are investigating the vasculature of the skeletal system, which controls fundamental processes such as bone formation and hematopoiesis. With the help of improved tissue processing, immunostaining and imaging protocols, we made a series of exciting and unexpected discoveries. This includes, for example, the characterization of specialized bone marrow compartments and of the interactions between endothelial, mesenchymal and hematopoietic cells.

Our work has also led to the identification of functional specialized capillaries and endothelial cell subtypes in bone, which promote osteogenesis and are important for the function of hematopoietic stem cells (Ramasamy et al. 2014, Nature; Kusumbe et al. 2016, Nature; Langen et al. 2017, Nat. Cell Biol.; Sivaraj et al. 2020, Elife). We found that these capillaries decline during aging, which contributes to age-related changes in bone mass and hematopoiesis (Kusumbe et al. 2014, Nature; Kusumbe et al. 2016, Nature). Other recent and ongoing projects address fetal bone marrow development, the role of the neurotransmitter dopamine in hematopoiesis, and the role of endothelial cells in bone marrow regeneration (Chen et al. 2019, Cell Stem Cell. 2019; Liu et al. 2021, Blood; Liu et al. 2022, Nat. Commun.). We are also using preclinical models for the development of therapeutic approaches promoting bone formation (Xu, Dinh et al., Elife 2022).

Endothelial cell biology

Projects in this area of research seek to identify and characterize the molecular pathways controlling endothelial cell sprouting, arteriovenous differentiation and vessel remodeling. Examples include the analysis of signaling by the Notch pathway (Benedito et al. 2009, Cell; Benedito et al. 2012, Nature), Eph receptor tyrosine kinases and their ephrin ligands (Wang et al. 2010, Nature), and VEGF receptor endocytosis in the growing vasculature (Nakayama et al. 2013, Nat. Cell Biol.). These projects made use of sophisticated cell type-specific and inducible genetic approaches in mice, which enable functional studies in the embryonic, postnatal and adult endothelium. More recently, we have used single cell RNA sequencing to gain insight into the heterogeneity of endothelial cells in the healthy and diseased brain (Jeong et al. 2022, Elife).

Arteries control blood flow and thereby many functional properties of the vascular system. Accordingly, malformed, malfunctional or obstructed arteries are the cause of numerous human diseases. With the exception of a few examples, such as the formation of the dorsal aorta and of the cardinal vein in the early embryo, many fundamental aspects of arterial morphogenesis remain poorly understood. Our work has identified specialized sprouting endothelial cells, so-called tip cells, as an unexpected source of arterial endothelium (Pitulescu et al. 2017, Nat. Cell Biol.; Xu et al. 2014, Nat. Commun.). We also discovered that Dll4-mediated Notch activation is not mediating the selection of tip cells, as was previously believed, but rather directs tip cell progeny into growing arteries. Ongoing and future work in this important area will explore the relevance of this process in different organs as well as in regeneration and disease processes.

Biology of pericytes and vascular smooth muscle cells

Pericytes and vascular smooth muscle cells are essential for vascular integrity and function. The precise roles, developmental origins, heterogeneity, and molecular regulation of these cells have been one of our major research interests for more than a decade. We have uncovered that the recruitment and functional incorporation of pericytes into the vessel wall is controlled by ephrin-B2, a ligand of Eph family receptor tyrosine kinases (Foo et al. 2006, Cell), and integrin family cell-matrix receptors (Abraham et al. 2008, Circ Res.; Kogata et al. 2009, Genes Dev). Subsequently, we have identified ephrin-B2 as a critical modulator of platelet-derived growth factor receptor β (PDGFRβ) internalization and signaling (Nakayama et al., 2013, Genes Dev.). Loss of the transcription factor RBPJ, a transcription factor in the Notch pathway, induces disease-promoting properties in brain pericytes (Dieguez-Hurtado 2019, Nat. Commun.). In another project, we have demonstrated that part of the pericytes and vascular smooth muscle cells in the developing heart are derived from endocardial cells (Chen et al. 2016, Nat. Commun.), which undergo endothelial-to-mesenchymal transition. In the postnatal lung, pericytes are a critical source of growth factor signals that control epithelial cell behavior and thereby alveogenesis (Kato et al. 2018, Nat. Commun.).

Genetic fate mapping and gene inactivation approaches in these and other studies have been facilitated by tamoxifen-inducible Pdgfrb-CreERT2 transgenic mice, which were generated in my group and are now freely available within the scientific community.


Transgenic mouse lines

Transgenic mice expressing tamoxifen-inducible CreERT2 recombinase in all endothelial cells (Cdh5-CreERT2), in the arterial endothelium (Bmx-CreERT2) are now available through the European Mouse Mutant Archive (EMMA):

The intellectual property for these mice is owned by Cancer Research UK, where the mice were originally generated, and therefore we cannot issue any MTAs.

To our knowledge, the Cdh5-CreERT2 transgenic construct (described in PMID: 20445537) has been inserted in multiple copies into chromosome 10, which should be considered for interbreeding with other mouse lines. An extensive list of references and other information for this mouse line can be found at

Esm1-CreERT2 transgenic animals for experiments in tip cells and other Esm1+ endothelial cells are available directly from our institute.


Selected publications

Selected publications on the biology of bone and marrow:

  • Liu Y, Chen Q, Jeong HW, Koh BI, Watson EC, Xu C, Stehling M, Zhou B, Adams RH (2022). A specialized bone marrow microenvironment for fetal haematopoiesis. Nat. Commun. 13:1327.
  • Xu C, Dinh VV, Kruse K, Jeong HW, Watson EC, Adams S, Berkenfeld F, Stehling M, Rasouli SJ, Fan R, Chen R, Bedzhov I, Chen Q, Kato K, Pitulescu ME, Adams RH (2022). Induction of osteogenesis by bone-targeted Notch activation. Elife 11:e60183.
  • Sivaraj KK, Majev PG, Jeong HW, Dharmalingam B, Zeuschner D, Schröder S, Bixel MG, Timmen M, Stange R, Adams RH (2022). Mesenchymal stromal cell-derived septoclasts resorb cartilage during developmental ossification and fracture healing. Nat. Commun. 13:571.
  • Tuckermann J, Adams RH (2021).The endothelium-bone axis in development, homeostasis and bone and joint disease. Nat. Rev. Rheumatol. 17:608-620.
  • Liu Y, Chen Q, Jeong HW, Han D, Fabian J, Drexler HCA, Stehling M, Schöler HR, Adams RH (2021). Dopamine signaling regulates hematopoietic stem and progenitor cell function. Blood 138:2051-2065.
  • Sivaraj KK, Jeong HW, Dharmalingam B, Zeuschner D, Adams S, Potente M, Adams RH (2021). Regional specialization and fate specification of bone stromal cells in skeletal development. Cell Rep. 36:109352.
  • Sivaraj KK, Dharmalingam B, Mohanakrishnan V, Jeong HW, Kato K, Schröder S, Adams S, Koh GY, Adams RH (2020). YAP1 and TAZ negatively control bone angiogenesis by limiting hypoxia-inducible factor signaling in endothelial cells. Elife 9:e50770.
  • Chen Q, Liu Y, Jeong HW, Stehling M, Dinh VV, Zhou B, Adams RH (2019). Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury. Cell Stem Cell 25:768-78.
  • Tikhonova AN, Dolgalev I, Hu H, Sivaraj KK, Hoxha E, Cuesta-Domínguez Á, Pinho S, Akhmetzyanova I, Gao J, Witkowski M, Guillamot M, Gutkin MC, Zhang Y, Marier C, Diefenbach C, Kousteni S, Heguy A, Zhong H, Fooksman DR, Butler JM, Economides A, Frenette PS, Adams RH, Satija R, Tsirigos A, Aifantis I (2019). The bone marrow microenvironment at single-cell resolution. Nature 569:222-228.
  • Watson EC, Adams RH (2018). Biology of Bone: The Vasculature of the Skeletal System. Cold Spring Harb. Perspect. Med. 8:a031559.
  • Kusumbe AP, Ramasamy SK, Itkin T, Andoloussi M, Langen UH, Betsholtz C, Lapidot T, Adams RH (2016). Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature 532:380-4.
  • Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK, Kusumbe AP, Ledergor G, Jung Y, Milo I, Poulos MG, Kalinkovich A, Ludin A, Kollet O, Shakhar G, Butler JM, Rafii S, Adams RH, Scadden DT, Lin CP, Lapidot T (2016). Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 532:323-8.
  • Kusumbe AP, Ramasamy SK, Starsichova A, Adams RH (2015). Sample preparation for high-resolution 3D confocal imaging of mouse skeletal tissue. Nat. Protoc. 10:1904-14.
  • Ramasamy SK, Kusumbe AP, Wang L, Adams RH (2014). Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507:376-80.
  • Kusumbe AP, Ramasamy SK, Adams RH (2014). Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507:323-8.
  • Wang L, Benedito R, Bixel MG, Zeuschner D, Stehling M, Sävendahl L, Haigh JJ, Snippert H, Clevers H, Breier G, Kiefer F, Adams RH (2012). Identification of a clonally expanding haematopoietic compartment in bone marrow. EMBO J. 32:219-30.


Selected publications on angiogenesis and endothelial biology:

  • Jeong HW, Diéguez-Hurtado R, Arf H, Song J, Park H, Kruse K, Sorokin L, Adams RH (2022). Single-cell transcriptomics reveals functionally specialized vascular endothelium in brain. Elife 11:e57520.
  • Park H, Yamamoto H, Mohn L, Ambühl L, Kanai K, Schmidt I, Kim KP, Fraccaroli A, Feil S, Junge HJ, Montanez E, Berger W, Adams RH (2019). Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy. Nat. Commun. 10:5243.
  • Luxán G, Stewen J, Díaz N, Kato K, Maney SK, Aravamudhan A, Berkenfeld F, Nagelmann N, Drexler HC, Zeuschner D, Faber C, Schillers H, Hermann S, Wiseman J, Vaquerizas JM, Pitulescu ME, Adams RH (2019). Endothelial EphB4 maintains vascular integrity and transport function in adult heart. Elife 8:e45863.
  • Del Monte-Nieto G, Ramialison M, Adam AAS, Wu B, Aharonov A, D'Uva G, Bourke LM, Pitulescu ME, Chen H, de la Pompa JL, Shou W, Adams RH, Harten SK, Tzahor E, Zhou B, Harvey RP (2018). Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation. Nature 557:439-445.
  • Yamamoto H, Ehling M, Kato K, Kanai K, van Lessen M, Frye M, Zeuschner D, Nakayama M, Vestweber D, Adams RH. (2015). Integrin β1 controls VE-cadherin localization and blood vessel stability. Nat. Commun. 6:6429.
  • Nakayama M, Nakayama A, van Lessen M, Yamamoto H, Hoffmann S, Drexler HC, Itoh N, Hirose T, Breier G, Vestweber D, Cooper JA, Ohno S, Kaibuchi K, Adams RH (2013). Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat. Cell. Biol. 15:249-60.
  • Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, Duarte A, Pytowski B, Adams RH (2012). Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484:110-4.
  • Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Lüthi U, Barberis A, Benjamin LE, Mäkinen T, Nobes CD, Adams RH (2010). Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465:483-486.
  • Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009). The Notch lingands DII4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124-35.
  • Roca C, Adams RH (2007). Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 21:2511-24.
  • Adams RH, Alitalo K (2007). Molecular regulation of angiogenesis and lymphangiogenesis. Nature Rev. Mol. Cell. Biol. 8:464-78.


Selected publications on mural cell biology:

  • Diéguez-Hurtado R, Kato K, Giaimo BD, Nieminen-Kelhä M, Arf H, Ferrante F, Bartkuhn M, Zimmermann T, Bixel MG, Eilken HM, Adams S, Borggrefe T, Vajkoczy P, Adams RH (2019). Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes. Nat. Commun. 10:2817.
  • Chen Q, Zhang H., Liu Y., Adams S., Eilken H., Stehling M., Corada M., Dejana E., Zhou B., Adams R.H. (2016). Endothelial cells are progenitors of cardiac pericytes and vascular smooth muscle cells. Nat. Commun. 7:12422.
  • Nakayama A, Nakayama M, Turner CJ, Höing S, Lepore JJ, Adams RH. (2013). Ephrin-B2 controls PDGFRβ internalization and signaling. Genes Dev. 27:2576-89.
  • Kogata N, Tribe RM, Fässler R, Way M, Adams RH (2009). Integrin-linked kinase controls vascular wall formation by negatively regulating Rho/ROCK-mediated vascular smooth muscle cell contraction. Genes Dev 23:2278-83.
  • Abraham S, Kogata N, Fässler R, Adams RH (2008). The integrin ß1 subunit controls mural cell adhesion, spreading and blood vessel wall stability. Circ. Res. 102:562-570.
  • Stenzel D, Nye E, Nisancioglu M, Adams RH, Yamaguchi Y, Gerhardt H (2009). Peripheral mural cell recruitment requires cell-autonomous heparan-sulfate. Blood 114:915-24.
  • Foo SS, Turner CJ, Adams S, Compagni A, Aubyn D, Kogata N, Lindblom P, Shani M, Zicha D, Adams RH (2006). Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124:161-173.


Complete lists of publications can be found on PubMed, ResearchGate and Web of Science:


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