How Vascular Endothelial Growth Factor-A (VEGF) Regulates Differentiation of Mesenchymal Stem Cells

Vascular endothelial growth factor A (VEGF), a key factor in angiogenesis, plays an essential role in skeletal development and postnatal homeostasis. VEGF serves as a survival factor for chondrocytes and couples the resorption of cartilage with bone formation during endochondral ossification. Recently, it has also been found to regulate the balance between osteoblast and adipocyte differentiation in bone marrow mesenchymal stem cells. Surprisingly, this regulatory function of VEGF is not based on paracrine signaling involving cell surface receptor activation. Instead, the mechanism appears to utilize intracellular VEGF, which is functionally linked to the nuclear envelope protein lamin A. Lamin A and VEGF control osteoblast and adipocyte differentiation by regulating the levels of the osteoblast and adipocyte transcription factors Runx2 and PPARγ, respectively. These data raise the intriguing possibility that loss of bone mass during aging may be manipulated by controlling the levels and activity of intracellular VEGF in bone marrow mesenchymal stem cells.