Development and pathologies of the arterial wall

Abstract

Arteries consist of an inner single layer of endothelial cells surrounded by layers of smooth muscle and an outer adventitia. The majority of vascular developmental studies focus on the construction of endothelial networks through the process of angiogenesis. Although many devastating vascular diseases involve abnormalities in components of the smooth muscle and adventitia (i.e., the vascular wall), the morphogenesis of these layers has received relatively less attention. Here, we briefly review key elements underlying endothelial layer formation and then focus on vascular wall development, specifically on smooth muscle cell origins and differentiation, patterning of the vascular wall, and the role of extracellular matrix and adventitial progenitor cells. Finally, we discuss select human diseases characterized by marked vascular wall abnormalities. We propose that continuing to apply approaches from developmental biology to the study of vascular disease will stimulate important advancements in elucidating disease mechanism and devising novel therapeutic strategies.

Fig. 1

Schematic diagram of development and lineage reprogramming of cells in the epigenetic landscape. In normal development, a pluripotent cell (green ball) rolls down bifurcating valleys, which represent all possible developmental paths. The cell makes a series of “choices” and differentiates into a mature cell (blue ball) at the bottom of the valley. Lineage reprogramming includes dedifferentiation and transdifferentiation, where a mature cell takes a step backward to a progenitor stage (cyan ball) or converts directly to another mature cell (yellow ball). Adapted from reference [6]

Fig. 2

The different embryological origins of aortic SMCs may contribute to the site of aortic dissection. Aortic SMCs originate from three distinct developmental lineages. The aortic root is derived from LPM (blue solid arrow), while the ascending aorta and arch are neural crest derived (red solid arrow). The descending aortic SMCs originate from PSM (green solid arrow). In vitro hESC-derived SMC subtypes predicted the differential MMP and TIMP activation in aortic SMCs of corresponding origins (dotted arrows) in response to IL-1β. The authors propose that the origin-specific SMCs display differential proteolytic ability in disease settings, which may result in differential loss of the structural integrity in different regions along the aortic wall. This difference in mechanical properties may predispose aortic dissection to occur preferentially at the boundaries between different SMC lineages (indicated by black jagged bolts). Figure from reference [67]

Fig. 3

Radial development of the pulmonary artery (PA) wall. Longitudinal sections through the left PA wall at the indicated ages in the embryonic mouse, stained for SMA (red), PDGFR-β (green), and nuclei (DAPI, blue) as indicated. Arrowheads, nuclei elongated longitudinally. The inset in E shows a transverse section through the left PA wall. Schematics at the bottom summarize SMA (red) and PDGFR-β (green) expression (orange, co-expression of SMA and PDGFR-β) and cell shape and orientation changes in the forming layers of the developing PA wall. E endothelial cell (EC) layer; 1 first (inner) smooth muscle cell (SMC) layer; 2 second SMC layer; A adventitial cell layer; Lu PA lumen. Square cells circumferentially-oriented cells. Scale bars 10 μm. Figure from reference [76]

Fig. 4

Clonal analysis of inner layer cells of the PA wall. a Clonal analysis scheme showing early (E11.5) marking of an inner layer cell and four possible patterns of its proliferation and migration: longitudinal (L), circumferential (C), and radial (R) expansion and longitudinal with mixing with unlabeled cells (L, M). E endothelial cell (EC) layer; 1, 2 first and second SMC layers; A adventitial cell layer. b A GFP-marked left PA clone in a SMMHC-CreER, ROSA26R ^mTmG/+ embryo, induced by a limiting dose of tamoxifen at E11.5 and analyzed at E13.5 after staining for clone marker (GFP, green), SMA (red), and PECAM (white). An individual coronal confocal section of the four-cell clone is shown (left panel) along with a maximal projection (center panel). 1–4 cells of clone; Lu PA lumen. In the clone schematic (right panel), the positions of marked cells are indicated by circles color-coded to highlight the layer in which the cell resides: green (layer 1), red (layer 2), and blue (adventitia). For cells located superficial (white circles) or deep (gray circles) to the lumen, we were unable to determine which layer they reside in (nd not determined). This clone expanded longitudinally (L) and circumferentially (C), with mixing (M). c Sixteen-cell clone, induced and analyzed as in b, except clone marker was multicolor (rainbow, Rb) ROSA26R^Rb Cre reporter and the clone was analyzed at E18.5. Left panel Cerulean channel of section: bright cells are Cerulean+ (numbered). Center panel Cerulean, mOrange and mCherry channels of the same section. All labeled cells in left PA express Cerulean marker, confirming clonality. Clone expanded in all three axes (L, C, and R), with some cells (red in schematic) having invaded layer 2. For clarity, only every other cell in the schematic is numbered. Figure adapted from reference [76]

Fig. 5

Signaling pathways mediating mural cell recruitment, differentiation, and vascular stabilization. Multiple ligand–receptor complexes have been implicated in pericyte recruitment to the endothelium, including PDGF-B/PDGFR-β, stromal-derived factor (SDF)-1α/C-X-C chemokine receptor type 4 (CXCR4), heparin binding epidermal growth factor (HB-EGF)/EGF receptors (ErbBs), Shh/patched (Ptc), and angiopoietin (Ang)1/Tie-2. The cellular response to TGFβ/TGFβ receptor signaling is dependent on receptor composition and relative ligand level. A ligand–receptor pair is indicated by the same color. N-cadherin and Notch-mediated vessel stabilization requires direct contact between a pericyte and an EC. Figure from reference [102]