PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation

VEGF induces normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo. This transition depends on the balance between VEGF-induced endothelial stimulation and PDGF-BB-mediated pericyte recruitment, and co-expression of PDGF-BB normalizes aberrant angiogenesis despite high VEGF doses. We recently found that VEGF over-expression induces angiogenesis in skeletal muscle through an initial circumferential vascular enlargement followed by longitudinal splitting, rather than sprouting. Here we investigated the cellular mechanism by which PDGF-BB co-expression normalizes VEGF-induced aberrant angiogenesis. Monoclonal populations of transduced myoblasts, expressing similarly high levels of VEGF alone or with PDGF-BB, were implanted in mouse skeletal muscles. PDGF-BB co-expression did not promote sprouting and angiogenesis that occurred through vascular enlargement and splitting. However, enlargements were significantly smaller in diameter, due to a significant reduction in endothelial proliferation, and retained pericytes, which were otherwise lost with high VEGF alone. A time-course of histological analyses and repetitive intravital imaging showed that PDGF-BB co-expression anticipated the initiation of vascular enlargement and markedly accelerated the splitting process. Interestingly, quantification during in vivo imaging suggested that a global reduction in shear stress favored the initiation of transluminal pillar formation during VEGF-induced splitting angiogenesis. Quantification of target gene expression showed that VEGF-R2 signaling output was significantly reduced by PDGF-BB co-expression compared to VEGF alone. In conclusion, PDGF-BB co-expression prevents VEGF-induced aberrant angiogenesis by modulating VEGF-R2 signaling and endothelial proliferation, thereby limiting the degree of circumferential enlargement and enabling efficient completion of vascular splitting into normal capillary networks despite high VEGF doses

A sliver of the past: The decimation of the genetic diversity of the Mexican wolf

The endangered Mexican wolf (Canis lupus baileyi) is known to carry exceedingly low levels of genetic diversity. This could be (i) the result of long-term evolutionary patterns as they exist at the southernmost limit of the species distribution at a relatively reduced effective size, or (ii) due to rapid population decline caused by human persecution over the last century. If the former, purifying selection is expected to have minimized the impact of inbreeding. If the latter, rapid and recent declines in genetic diversity may have resulted in severe fitness consequences. To differentiate these hypotheses, we conducted comparative whole-genome analyses of five historical Mexican wolves (1907–1917) and 18 contemporary Mexican and grey wolves from North America and Eurasia. Based on whole-genome data, historical and modern Mexican wolves together form a discrete unit. Moreover, we found that modern Mexican wolves have reduced genetic diversity and increased inbreeding relative to the historical population, which was widespread across the southwestern United States and not restricted to Mexico as previously assumed. Finally, although Mexican wolves have evolved in sympatry with coyotes (C. latrans), we observed lower introgression between historical Mexican wolves and coyotes than with modern Mexican wolves, despite similarities in body size. Taken together, our data show that recent population declines probably caused the reduced level of genetic diversity, but not the observed differentiation of the Mexican wolves from other North American wolvesPeer reviewe