Bidirectional electrical communication between smooth muscle and endothelial cells in the pig coronary artery

Using strips of the left descending branch of the pig coronary artery in vitro, we show that smooth muscle cells are hyperpolarized by isoproterenol, a beta-agonist, independently of the presence or absence of intact endothelium. This hyperpolarization is transmitted to the lining endothelial cells in intact coronary strips. On the contrary, the cultured endothelial cells, without contact with smooth muscles, are not hyperpolarized by the beta-agonist. This shows that, in addition to the hyperpolarizations that flow from the endothelium to the media in response to kinins, electrical signals are also transmitted in the opposite direction, from the smooth muscles to the lining endothelial cells. In an attempt to test whether electrical coupling through gap junctions is implicated in the transmission of hyperpolarizations between the endothelial and the smooth muscle cells, we used halothane, a gap junction uncoupler. We observed that halothane does not inhibit the transmission of kinin hyperpolarizations from the endothelium to the smooth muscles, whereas it inhibits the transmission of isoproterenol hyperpolarization in the reverse direction

Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration

The hypoxia-inducible factor-1α (HIF-1α) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1α pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1α activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1α in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro. One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1α pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing

Biological mechanisms of bone and cartilage remodelling—genomic perspective

Rapid advancements in the field of genomics, enabled by the achievements of the Human Genome Project and the complete decoding of the human genome, have opened an unimaginable set of opportunities for scientists to further unveil delicate mechanisms underlying the functional homeostasis of biological systems. The trend of applying whole-genome analysis techniques has also contributed to a better understanding of physiological and pathological processes involved in homeostasis of bone and cartilage tissues. Gene expression profiling studies have yielded novel insights into the complex interplay of osteoblast and osteoclast regulation, as well as paracrine and endocrine control of bone and cartilage remodelling. Mechanisms of new bone formation responsible for fracture healing and distraction osteogenesis, as well as healing of joint cartilage defects, have also been extensively studied. Microarray experiments have been especially useful in studying pathological processes involved in diseases such as osteoporosis or bone tumours. Existing results show that microarrays hold great promise in areas such as identification of targets for novel therapies or development of new biomarkers and classifiers in skeletal diseases