About

Arndt Siekmann is an Associate Professor of Cell and Developmental Biology at the University of Pennsylvania's Perelman School of Medicine. He holds a Ph.D. in Molecular Cell Biology and Genetics from the Max Planck Institute and a B.S. in Biology from Albert-Ludwigs-Universität Freiburg. His research focuses on vascular biology, including the biology of vascular mural cells, the mechanisms governing blood vessel network expansion, and the regulation of endothelial cell proliferation. His work involves studying these processes in model organisms such as zebrafish to understand the morphogenetic and signaling pathways that shape vascular development and function.

Research topics

• Computer Science
• Chemistry
• Computational biology
• Cell biology
• Nanotechnology
• Neuroscience
• Biology
• Materials science

Selected publications

• Alk1/Endoglin signaling restricts vein cell size increases in response to hemodynamic cues and limits ribosomal biogenesis

  Research Square · 2024-05-24

  preprintOpen accessSenior author
  PublisherDOI

• Alk1/Endoglin signaling restricts vein cell size increases in response to hemodynamic cues

  Angiogenesis · 2024-12-10 · 5 citations

  articleOpen accessSenior author

  Hemodynamic cues are thought to control blood vessel hierarchy through a shear stress set point, where flow increases lead to blood vessel diameter expansion, while decreases in blood flow cause blood vessel narrowing. Aberrations in blood vessel diameter control can cause congenital arteriovenous malformations (AVMs). We show in zebrafish embryos that while arteries behave according to the shear stress set point model, veins do not. This behavior is dependent on distinct arterial and venous endothelial cell (EC) shapes and sizes. We show that arterial ECs enlarge more strongly when experiencing higher flow, as compared to vein cells. Through the generation of chimeric embryos, we discover that this behavior of vein cells depends on the bone morphogenetic protein (BMP) pathway components Endoglin and Alk1. Endoglin (eng) or alk1 (acvrl1) mutant vein cells enlarge when in normal hemodynamic environments, while we do not observe a phenotype in either acvrl1 or eng mutant ECs in arteries. We further show that an increase in vein diameters initiates AVMs in eng mutants, secondarily leading to higher flow to arteries. These enlarge in response to higher flow through increasing arterial EC sizes, fueling the AVM. This study thus reveals a mechanism through which BMP signaling limits vein EC size increases in response to flow and provides a framework for our understanding of how a small number of mutant vein cells via flow-mediated secondary effects on wildtype arterial ECs can precipitate larger AVMs in disease conditions, such as hereditary hemorrhagic telangiectasia (HHT).

  PublisherOA PDFDOI

• Alk1/Endoglin dependent increases in vein endothelial cell sizes precipitate arteriovenous malformations

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-11-08 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Aberrations in blood vessel diameters can disrupt the hierarchical patterning of the vasculature and cause congenital vascular anomalies, such as arteriovenous malformations (AVMs). Despite the identification of the Bone Morphogenetic Protein (BMP) pathway as a major driver in AVM pathology, we still lack an understanding of the early embryonic events regulating vessel hierarchy and arteriovenous shunt formation in vivo . We therefore studied blood vessel diameter control of the dorsal aorta (DA) and posterior cardinal vein (PCV) in zebrafish embryos. Our findings reveal that increases in blood flow during embryonic development result in increases in arterial endothelial cell (EC) sizes, ultimately enlarging DA diameters. By contrast, anterior regions of the PCV did not respond to changes in blood flow, while caudal regions, close to the artery-vein junction, responded to changes in flow like the DA, but to a lesser extent. To unravel the mechanisms underlying the reduced response of PCV ECs to flow, we studied zebrafish embryos mutant for the BMP pathway components endoglin and alk1 . Through the generation of genetic mosaics, we discovered that both Endoglin and Alk1 were required cell autonomously in PCV cells to restrict EC sizes and thereby limit venous diameter increases in response to flow. We further revealed that initial increases in the diameter of the caudal PCV secondarily led to increased DA diameters and cell sizes. Therefore, Alk1/Endoglin signaling prevents vein ECs from behaving like arterial ECs. This differential response of arterial and venous EC cells to increases in flow is necessary to prevent the development of AVMs. This study thus offers insights into the spatiotemporal regulation of vessel hierarchy during early development and identifies changes in EC shapes as an important contributor in determining blood vessel diameters. Failure in this mechanism underlies the vein-specific initiation of AVMs in vertebrate models of HHT.

  PublisherOA PDFDOI

• Biology of vascular mural cells

  Development · 2023-08-15 · 39 citations

  reviewOpen access1st authorCorresponding

  The vasculature consists of vessels of different sizes that are arranged in a hierarchical pattern. Two cell populations work in concert to establish this pattern during embryonic development and adopt it to changes in blood flow demand later in life: endothelial cells that line the inner surface of blood vessels, and adjacent vascular mural cells, including smooth muscle cells and pericytes. Despite recent progress in elucidating the signalling pathways controlling their crosstalk, much debate remains with regard to how mural cells influence endothelial cell biology and thereby contribute to the regulation of blood vessel formation and diameters. In this Review, I discuss mural cell functions and their interactions with endothelial cells, focusing on how these interactions ensure optimal blood flow patterns. Subsequently, I introduce the signalling pathways controlling mural cell development followed by an overview of mural cell ontogeny with an emphasis on the distinguishing features of mural cells located on different types of blood vessels. Ultimately, I explore therapeutic strategies involving mural cells to alleviate tissue ischemia and improve vascular efficiency in a variety of diseases.

  PublisherOA PDFDOI

• Temporally and regionally distinct morphogenetic processes govern zebrafish caudal fin blood vessel network expansion

  Development · 2023-03-20 · 4 citations

  articleOpen accessSenior author

  Blood vessels form elaborate networks that depend on tissue-specific signalling pathways and anatomical structures to guide their growth. However, it is not clear which morphogenetic principles organize the stepwise assembly of the vasculature. We therefore performed a longitudinal analysis of zebrafish caudal fin vascular assembly, revealing the existence of temporally and spatially distinct morphogenetic processes. Initially, vein-derived endothelial cells (ECs) generated arteries in a reiterative process requiring vascular endothelial growth factor (Vegf), Notch and cxcr4a signalling. Subsequently, veins produced veins in more proximal fin regions, transforming pre-existing artery-vein loops into a three-vessel pattern consisting of an artery and two veins. A distinct set of vascular plexuses formed at the base of the fin. They differed in their diameter, flow magnitude and marker gene expression. At later stages, intussusceptive angiogenesis occurred from veins in distal fin regions. In proximal fin regions, we observed new vein sprouts crossing the inter-ray tissue through sprouting angiogenesis. Together, our results reveal a surprising diversity among the mechanisms generating the mature fin vasculature and suggest that these might be driven by separate local cues.

  PublisherOA PDFDOI

• Regenerating vascular mural cells in zebrafish fin blood vessels are not derived from pre-existing mural cells and differentially require Pdgfrb signalling for their development

  Development · 2022-03-17 · 21 citations

  articleOpen accessSenior author

  Vascular networks comprise endothelial cells and mural cells, which include pericytes and smooth muscle cells. To elucidate the mechanisms controlling mural cell recruitment during development and tissue regeneration, we studied zebrafish caudal fin arteries. Mural cells colonizing arteries proximal to the body wrapped around them, whereas those in more distal regions extended protrusions along the proximo-distal vascular axis. Both cell populations expressed platelet-derived growth factor receptor β (pdgfrb) and the smooth muscle cell marker myosin heavy chain 11a (myh11a). Most wrapping cells in proximal locations additionally expressed actin alpha2, smooth muscle (acta2). Loss of Pdgfrb signalling specifically decreased mural cell numbers at the vascular front. Using lineage tracing, we demonstrate that precursor cells located in periarterial regions and expressing Pgdfrb can give rise to mural cells. Studying tissue regeneration, we did not find evidence that newly formed mural cells were derived from pre-existing cells. Together, our findings reveal conserved roles for Pdgfrb signalling in development and regeneration, and suggest a limited capacity of mural cells to self-renew or contribute to other cell types during tissue regeneration.

  PublisherOA PDFDOI

• Shear stress switches the association of endothelial enhancers from ETV/ETS to KLF transcription factor binding sites

  Scientific Reports · 2022-03-21 · 35 citations

  articleOpen accessSenior author

  Endothelial cells (ECs) lining blood vessels are exposed to mechanical forces, such as shear stress. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation. Despite a good understanding of the genes responding to shear stress, our insight into the transcriptional regulation of these genes is much more limited. Here, we set out to study alterations in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 h of laminar shear stress. Our results show a correlation of gained and lost enhancers with up and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized the shear stress response in ECs of zebrafish embryos using RNA-Seq. Our results lay the groundwork for the exploration of shear stress responsive elements in controlling EC biology.

  PublisherOA PDFDOI

• Temporally and regionally distinct morphogenetic processes govern zebrafish tail fin blood vessel network expansion

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-06-16

  preprintOpen accessSenior authorCorresponding

  Abstract Blood vessels form elaborate networks depending on tissue-specific signalling pathways and anatomical structures to guide their growth. However, it is not clear which morphogenetic principles organize the stepwise assembly of the vasculature. We thus performed a longitudinal analysis of zebrafish tail fin vascular assembly, revealing the existence of temporally and spatially distinct morphogenetic processes. Initially, vein-derived endothelial cells (ECs) generated arteries in a reiterative process requiring Vascular Endothelial Growth Factor (VEGF), Notch and cxcr4a signalling. Subsequently, veins produced veins in more proximal fin regions, transforming pre-existing artery-vein loops into a three-vessel pattern consisting of an artery and two veins. A distinct set of vascular plexuses formed at the base of the fin. They differed by virtue of diameter, flow magnitude and marker gene expression. At later stages, intussusceptive angiogenesis occurred from veins in distal fin regions. In proximal fin regions, we observed new vein sprouts crossing the inter-ray tissue through sprouting angiogenesis. Together, our results reveal a surprising diversity among the mechanisms generating the mature fin vasculature and suggest that these might be driven by separate local cues.

  PublisherOA PDFDOI

• Zebrafish mutants in vegfab can affect endothelial cell proliferation without altering ERK phosphorylation and are phenocopied by loss of PI3K signaling

  Developmental Biology · 2022-03-23 · 23 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Temperature-responsive optogenetic probes of cell signaling

  Nature Chemical Biology · 2021 · 56 citations

  • Computer Science
  • Chemistry
  • Cell biology
  PublisherOA PDFDOI

Recent grants

• Endothelial cell autonomous mechanisms of blood vessel diameter control

  NIH · $1.7M · 2020–2024

Frequent coauthors

• Jeroen Bussmann

  Centre for Human Drug Research

  67 shared

• Nathan D. Lawson

  University of Massachusetts Chan Medical School

  65 shared

• John C. Moore

  53 shared

• Stefan Schulte‐Merker

  53 shared

• Inmaculada Segura

  50 shared

• Giovanni Mariggi

  50 shared

• Jean-Michel Foidart

  University of Liège

  50 shared

• Karlien Hermans

  50 shared