Lack of Pericytes Leads to Endothelial Hyperplasia and Abnormal Vascular Morphogenesis

By M. Hellström, Holger Gerhardt, M. Kalén, Xuri Li, U. Eriksson, H. Wolburg, C. Betsholtz. Journal of Cell Biology, 2001

1,093 citations recorded by the source corpus.

The association of pericytes (PCs) to newly formed blood vessels has been suggested to regulate endothelial cell (EC) proliferation, survival, migration, differentiation, and vascular branching. Here, we addressed these issues using PDGF-B– and PDGF receptor-β (PDGFR-β)–deficient mice as in vivo models of brain angiogenesis in the absence of PCs. Quantitative morphological analysis showed that these mutants have normal microvessel density, length, and number of branch points. However, absence of PCs correlates with endothelial hyperplasia, increased capillary diameter, abnormal EC shape and ultrastructure, changed cellular distribution of certain junctional proteins, and morphological signs of increased transendothelial permeability. Brain endothelial hyperplasia was observed already at embryonic day (E) 11.5 and persisted throughout development. From E 13.5, vascular endothelial growth factor-A (VEGF-A) and other genes responsive to metabolic stress became upregulated, suggesting that the abnormal microvessel architecture has systemic metabolic consequences. VEGF-A upregulation correlated temporally with the occurrence of vascular abnormalities in the placenta and dilation of the heart. Thus, although PC deficiency appears to have direct effects on EC number before E 13.5, the subsequent increased VEGF-A levels may further abrogate microvessel architecture, promote vascular permeability, and contribute to formation of the edematous phenotype observed in late gestation PDGF-B and PDGFR-β knock out embryos.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/a60b851dcac73f86824d6bcfc09ae206e8466fb0

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Citations in the corpus

Molecular regulation of vessel maturation (2003, background): “Although PDGFB is expressed by a number of cells, including ECs and mural cells, signaling through PDGFR-β, which is expressed on mural cells, is responsible for their proliferation and migration during vascular maturatio”
Intraventricular Hemorrhage in Premature Infants: Mechanism of Disease (2010, background): “The rounded contour of the blood vessel in cross-section indicates immaturity of the germinal matrix vasculature (21).”
Prespecification and plasticity: shifting mechanisms of cell migration. (2004, background): “Sprouting blood vessels, unlike other groups of cells undergoing collective migration, use cadherins to recruit pericytes as a second cell type; these pericytes then participate in the de novo synthesis of an encircling basement membrane [43,44].”
Roles of PDGF in animal development (2003, background): “Consequently, endothelial sprouts hyperproliferate and give rise to dilated, ectopic capillaries that are unstable, hyperpermeable and vulnerable to degeneration or regression (Lindahl et al., 1997a; Hellström et al., 2001; Enge et al., 2002).”
Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. (2004, positive): “Blood vessels in mice deficient in PDGF-B or PDGFR- do not recruit pericytes and have abnormalities reminiscent of those of tumor vessels.(10,48) Treatment with AG013736 or VEGF-Trap normalized the phenotype of some pericytes, as manifested by a tighter association with endothelial cells of survivin”
Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. (2003, background): “Analyses of knock-out mice for PDGF-B and PDGFR- have shown that PDGF-B signaling via PDGFR- is critically involved in recruitment of pericytes and vascular smooth muscle cells (vSMCs) to blood vessels (Lindahl et al. 1997; Hellström et al. 1999, 2001).”
Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. (2002, background): “Moreover, unlike the vessels of embryos lacking heparin-binding VEGF-A, those of PDGF-B and PDFGR- knockouts are not impaired in branching (Hellstrom et al. 2001; C. Ruhrberg and D.T. Shima, unpubl.).”
Diabetes and Wound Angiogenesis (2017, background): “PDGF-β deficient embryos show insufficient mural cell recruitment, resulting in uncontrolled EC development, vessel enlargement, permeability, and impaired perfusion [22,23].”
Cellular abnormalities of blood vessels as targets in cancer. (2005, background): “Mice genetically deficient in PDGF-B or its receptors have blood vessels with loose pericyte attachment, irregular vessel caliber, luminal projections of endothelial cells, and hemorrhage [31,32].”