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.). 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).

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.

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.). 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 commercially available:

Alternatively, MTAs can be obtained via:

Mice for constitutive (Cre) or tamoxifen-inducible (CreERT2) experiments in PDGFRβ+ cells are available here:


Selected publications

Selected publications on the biology of bone and marrow:

  • Langen UH, Pitulescu ME, Kim JM, Enriquez-Gasca R, Sivaraj KK, Kusumbe AP, Singh A, Di Russo J, Bixel MG, Zhou B, Sorokin L, Vaquerizas JM, Adams RH. (2017). Cell-matrix signals specify bone endothelial cells during developmental osteogenesis. Nat. Cell Biol. 19:189-201.
  • Bixel MG, Kusumbe AP, Ramasamy SK, Sivaraj KK, Butz S, Vestweber D, Adams RH. (2017). Flow Dynamics and HSPC Homing in Bone Marrow Microvessels. Cell Rep. 18:1804-1816.
  • Ramasamy SK, Kusumbe AP, Schiller M, Zeuschner D, Bixel MG, Milia C, Gamrekelashvili J, Limbourg A, Medvinsky A, Santoro MM, Limbourg FP, Adams RH. (2016). Blood flow controls bone vascular function and osteogenesis. Nat. Commun. 7:13601.
  • Sivaraj KK, Adams RH. (2016). Blood vessel formation and function in bone. Development. 143:2706-15.
  • Ramasamy SK, Kusumbe AP, Itkin T, Gur-Cohen S, Lapidot T, Adams RH. (2016). Regulation of Hematopoiesis and Osteogenesis by Blood Vessel-Derived Signals. Annu. Rev. Cell Dev. Biol. 32:649-675.
  • Kusumbe AP, Ramasamy SK, Itkin T, Mäe MA, Langen UH, Betsholtz C, Lapidot T, Adams RH. (2016). Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature 532:380-4.
  • 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, Adams RH. (2015). Regulation of tissue morphogenesis by endothelial cell-derived signals. Trends Cell Biol. 25:148-57.
  • Ramasamy SK, Kusumbe AP, Wang L, Adams RH. (2014). Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507:376-380.
  • Kusumbe AP, Ramasamy SK, Adams RH. (2014). Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507:323-328.
  • 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.
  • Wieland I, Jakubiczka S, Muschke P, Cohen M, Thiele H, Gerlach KL, Adams RH, Wieacker P. (2004). Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am. J. Hum. Genet. 74:1209-15.
  • Compagni A, Logan M, Klein R, Adams RH. (2003). Control of skeletal patterning by ephrinB1-EphB interactions. Dev Cell. 5:217-30.

Selected publications on angiogenesis and endothelial biology:

  • Jeong HW, Hernández-Rodríguez B, Kim J, Kim KP, Enriquez-Gasca R, Yoon J, Adams S, Schöler HR, Vaquerizas JM, Adams RH. (2017). Transcriptional regulation of endothelial cell behavior during sprouting angiogenesis. Nat Commun. 8:726.
  • Pitulescu ME, Schmidt I, Giaimo BD, Antoine T, Berkenfeld F, Ferrante F, Park H, Ehling M, Biljes D, Rocha SF, Langen UH, Stehling M, Nagasawa T, Ferrara N, Borggrefe T, Adams RH. (2017). Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat. Cell Biol. 19:915-927.
  • 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.
  • Xu C, Hasan SS, Schmidt I, Rocha SF, Pitulescu ME, Bussmann J, Meyen D, Raz E, Adams RH, Siekmann AF. (2014). Arteries are formed by vein-derived endothelial tip cells. Nat. Commun. 5:5758.
  • Pitulescu ME, Adams RH. (2014). Regulation of signaling interactions and receptor endocytosis in growing blood vessels. Cell Adh Migr. 8:366-77.
  • Rocha SF, Schiller M, Jing D, Li H, Butz S, Vestweber D, Biljes D, Drexler HC, Nieminen-Kelhä M, Vajkoczy P, Adams S, Benedito R, Adams RH. (2014). Esm1 modulates endothelial tip cell behavior and vascular permeability by enhancing VEGF bioavailability. Circ Res. 115:581-90.
  • Ehling M, Adams S, Benedito R, Adams RH. (2013). Notch controls retinal blood vessel maturation and quiescence. Development. 140:3051-61.
  • 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.
  • Pitulescu ME, Adams RH. (2010). Eph/ephrin molecules – a hub for signaling and endocytosis. Genes Dev. 24:2480-92.
  • Eilken HM, Adams RH. (2010). Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr. Opin. Cell Biol. 22:617-25.
  • Pitulescu ME, Schmidt I, Benedito R, Adams RH. (2010). Inducible gene targeting in the neonatal vasculature and analysis of retinal angiogenesis in mice. Nat. Protoc. 5:1518-34.
  • Adams RH, Eichmann A. (2010). Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol. 2:a001875.
  • 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 ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124-1135.
  • 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:

  • Kato K, Diéguez-Hurtado R, Park DY, Hong SP, Kato-Azuma S, Adams S, Stehling M, Trappmann B, Wrana JL, Koh GY, Adams RH. (2018). Pulmonary pericytes regulate lung morphogenesis. Nat. Commun. 9:2448.
  • Eilken HM, Diéguez-Hurtado R, Schmidt I, Nakayama M, Jeong HW, Arf H, Adams S, Ferrara N, Adams RH. (2017). Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1. Nat. Commun. 8:1574.
  • Chen Q, Zhang H, Liu Y, Adams S, Eilken H, Stehling M, Corada M, Dejana E, Zhou B, Adams RH. (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 beta1 subunit controls mural cell adhesion, spreading and blood vessel wall stability. Circ. Res. 102:562-570.
  • 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 and ResearchGate:

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