RESUMEN
Fibroblast growth factor 9 (FGF9) was first identified during a screen for factors acting on cells of the central nervous system (CNS). Research over the subsequent two decades has revealed this protein to be a critically important and elegantly regulated growth factor. A hallmark control feature is reciprocal compartmentalization, particularly during development, with epithelium as a dominant source and mesenchyme a prime target. This mesenchyme selectivity is accomplished by the high affinity of FGF9 to the IIIc isoforms of FGFR1, 2, and 3. FGF9 is expressed widely in the embryo, including the developing heart and lungs, and more selectively in the adult, including the CNS and kidneys. Global Fgf9-null mice die shortly after birth due to respiratory failure from hypoplastic lungs. As well, their hearts are dilated and poorly vascularized, the skeleton is small, the intestine is shortened, and male-to-female sex reversal can be found. Conditional Fgf9-null mice have revealed CNS phenotypes, including ataxia and epilepsy. In humans, FGF9 variants have been found to underlie multiple synostoses syndrome 3, a syndrome characterized by multiple joint fusions. Aberrant FGF9 signaling has also been implicated in differences of sex development and cancer, whereas vascular stabilizing effects of FGF9 could benefit chronic diseases. This primer reviews the attributes of this vital growth factor.
RESUMEN
Efforts to promote sprouting angiogenesis in skeletal muscles of individuals with peripheral artery disease have not been clinically successful. We discovered that, contrary to the prevailing view, angiogenesis following ischemic muscle injury in mice was not driven by endothelial sprouting. Instead, real-time imaging revealed the emergence of wide-caliber, primordial conduits with ultralow flow that rapidly transformed into a hierarchical neocirculation by transluminal bridging and intussusception. This process was accelerated by inhibiting vascular endothelial growth factor receptor-2 (VEGFR2). We probed this response by developing the first live-cell model of transluminal endothelial bridging using microfluidics. Endothelial cells subjected to ultralow shear stress could reposition inside the flowing lumen as pillars. Moreover, the low-flow lumen proved to be a privileged location for endothelial cells with reduced VEGFR2 signaling capacity, as VEGFR2 mechanosignals were boosted. These findings redefine regenerative angiogenesis in muscle as an intussusceptive process and uncover a basis for its launch.
