Endothelial-Mural Cell Signaling in Vascular Development and Angiogenesis

Abstract

Abstract-Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFR␤-dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-␤-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

“…The high proportion of Tomato + GFP + ECs at E15, 5 days after the loss of YS hemogenic activity, therefore suggests active expression of Pdgfrb‐Cre in the ECs. This is unexpected since Pdgfrb expression has not been previously reported in ECs, and it is thought to be exclusively expressed in mural and subsets of mesenchymal cells (Andrae et al, 2008; Gaengel et al, 2009). We cannot exclude the possibility that the endothelial activity of the Pdgfrb‐Cre line reflects recent tracing from an unknown source of Pdgfrb expressing EC progenitors or a transient endothelial expression of Pdgfrb .…”

Lung Pericytes and Resident Fibroblasts

“…39 A subset of FoxD1 þ progenitors differentiates into a-SMA þ VSMCs sheathing arterioles, reflecting a common mesenchymal origin and late divergence in ontogeny with pericytes. 2,3,18 VSMCs excluded, approximately 80% of the FoxD1-traced cells did not express Col1 or a-SMA but fit the definition of pericytes: stellate shaped with long cell processes, attached to endothelial cells, separated from the airways, exclusively PDGFR-b þ , 60% NG2 þ , and composing 5% to 15% of lung's cells. The similarly abundant FoxD1 À / Col1 þ cells were not pericytes in adults.…”

“…5,6,18 The receptor, PDGFR-b, marks pericytes and establishes their interactions with endothelial cells. Endothelial cells produce its ligand PDGF-B when sprouting, to which the pericytes respond by proliferating and migrating to attach to and cover the growing vessel.…”

“…Ang-1 matures and stabilizes the endothelium, increasing its integrity, and also enables new blood vessels to sprout and grow without leaking. 3,5,18,46 Unlike the PDGF pathway, disconnecting Ang-1 from Tie-2 does not interfere with pericyte positioning or reduce their vascular coverage, although it does alter the number and proportions of vessels during embryonic development. 3,5,43 Instead, targeted Ang-1 deficiency exacerbated fibrosis in response to physical damage or vascular stress, implying that the Ang-1/Tie2 connection between pericytes and endothelial cells regulates their coordinated response to injury.…”

“…However, the TGF-b pathway is so broadly engaged in development and pathogenesis in all organs, including its potential to stimulate opposing effects in angiogenesis, that without data from inducible, cell typee specific inhibition experiments, it remains problematic to assign discrete, TGF-bedependent roles to lung pericytes in vascular biology. 3,5,18,53 Pericytes sense vasoactive molecules and neurotransmitters, and one of their first proposed functions was to control blood flow by regulating the diameter of capillary vessels. 3 Ang-1 overexpression did increase capillary diameter, although whether periyctes could exert sufficient mechanical force to squeeze or stretch a capillary structure has been debated.…”