Imaging vascular development in zebrafish (Danio rerio)

Formation of a functional vascular network is a prerequisite for physiological organ function in vertebrates. Pathological vascularization furthermore plays a role in several human diseases, such as diabetic retinopathy, cardiovascular disease and cancer. Understanding the mechanisms governing embryonic vascular development may give more insight into pathological vascularization. Vascular development has classically been subdivided into two subcategories: (1) vasculogenesis - the de novo creation of vessels from angioblast precursors and (2) angiogenesis - the creation of blood vessels from preexisting vessels. Although a large number of studies have been performed on vascular development, several biological mechanisms behind both angio- and vasculogenesis remain unresolved.

The aim of Paper I was to analyze the role of Angiomotin-like protein 1 (AmotL1) in developmental angiogenesis. We showed that AmotL1 is an important mediator of endothelial cell junction formation in vivo.

In Paper II, we show (in vivo, ex vivo and in vitro) that Shingosine-1-phosphate receptor 1 (S1PR1) is a critical negative regulator of angiogenic sprouting. S1PR1 loss of function causes endothelial hypersprouting both in mouse and zebrafish, whereas activation inhibits sprouting and enhances cellular adhesion. This article shows how a blood borne signal (S1P) induces vascular stabilization via S1PR1, junctional VE-cadherin and inhibition of VEGFR2 signaling.

In Paper III, individual cell tracking of precursors originating in the LPM confirmed that precursors migrate to the midline in two waves in accordance with cell identity. Arterial-venous specification appears to occur in the lateral plate mesoderm (LPM), whereupon sprinting (fast migrating) precursors migrate to dorsal positions at the midline – forming the dorsal aorta (DA). Although the bulk of asymmetrical divisions presumably occurs in the LPM, some hemangioblasts continue to divide asymmetrically at least once during axial vessel formation.

List of scientific papers

I. Angiomotin-like protein 1 controls endothelial polarity and junction stability during sprouting angiogenesis. Zheng Y, Vertuani S, Nyström S, Audebert S, Meijer I, Tegnebratt T, Borg JP, Uhlén P, Majumdar A, Holmgren L. Circ Res. 2009 Jul 31; 105(3):260-70.
https://doi.org/10.1161/CIRCRESAHA.109.195156.

II. The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2. Gaengel K, Niaudet C, Hagikura K, Laviña B, Muhl L, Hofmann JJ, Ebarasi L, Nyström S, Rymo S, Chen LL, Pang MF, Jin Y, Raschperger E, Roswall P, Schulte D, Benedito R, Larsson J, Hellström M, Fuxe J, Uhlén P, Adams R, Jakobsson L, Majumdar A, Vestweber D, Uv A, Betsholtz C. Dev Cell. 2012 Sep 11; 23(3):587-99.
https://doi.org/1016/j.devcel.2012.08.005.

III. Arterial-venous and hematopoietic specification during zebrafish vasculogenesis - differences in precursor migration speed, guidance and potency. Nyström S, Majumdar A, Uhlén P, Holmgren L. [Manuscript]