History of discovery: platelet-derived growth factor.

A growth-promoting activity released from activated platelets, the platelet-derived growth factor, was discovered and characterized while the cellular and molecular mechanisms underlying the formation of the lesions of atherosclerosis were being investigated. This review provides a personal account of the different challenges we faced 3 decades ago in this undertaking and describes how our path was influenced by our focus on a disease process and by the evolving general understanding of the molecular effectors of cell proliferation.

The neurosecretory vesicle protein phogrin functions as a phosphatidylinositol phosphatase to regulate insulin secretion.

Phogrin is a transmembrane protein expressed in cells with stimulus-coupled peptide hormone secretion, including pancreatic beta cells, in which it is localized to the membrane of insulin-containing dense-core vesicles. By sequence, phogrin is a member of the family of receptor-like protein-tyrosine phosphatases, but it contains substitutions in conserved catalytic sequences, and no significant enzymatic activity for phogrin has ever been reported. We report here that phogrin is able to dephosphorylate specific inositol phospholipids, including phosphatidylinositol (PI) 3-phosphate and PI 4,5-diphosphate but not PI 3,4,5-trisphosphate.

Diabetes and aging alter bone marrow contributions to tissue maintenance.

Bone marrow-derived cells contribute to repair of injured tissue and to the maintenance of tissue homeostasis, but the extent to which perturbations of systemic homeostasis modulate this contribution is unknown. Accordingly, hematopoietic chimeras were used to determine contributions of bone marrow-derived cells to hepatocytes, skeletal muscle myocytes, and cardiomyocytes in healthy young, healthy old, and young obese diabetic mice. Mice with multiple genomic copies of a non-expressed β-globin/pBR322 sequence served as bone marrow donors.

Vasodilator-stimulated phosphoprotein regulates proliferation and growth inhibition by nitric oxide in vascular smooth muscle cells.

Objective: Vasodilator-stimulated phosphoprotein (VASP) was identified as a substrate for cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA). It is preferentially phosphorylated at serine239 by PKG, whereas serine157 is a preferred phosphorylation site for PKA. In addition, serine157 is phosphorylated by PKC in response to serum.

Fas and Fas-associated death domain protein regulate monocyte chemoattractant protein-1 expression by human smooth muscle cells through caspase- and calpain-dependent release of interleukin-1alpha.

We previously reported that treatment of human vascular smooth muscle cells (SMCs) with proapoptotic stimuli, including Fas ligand plus cycloheximide (FasL/Chx), or overexpression of Fas-associated death domain protein (FADD) result in increased expression of monocyte chemoattractant protein-1 (MCP-1) and other proinflammatory genes. In this study, we demonstrate that Fas/FADD-induced MCP-1 upregulation is driven by an autocrine/paracrine signaling loop in which interleukin (IL)-1alpha synthesis and release are activated through caspase- and calpain-dependent processes. Untreated SMCs contain very little IL-1alpha protein or transcript.

Chimera analysis supports a predominant role of PDGFRbeta in promoting smooth-muscle cell chemotaxis after arterial injury.

The carotid artery shows a common response to many forms of injury, including a rapid activation of smooth muscle cell (SMC) proliferation in the media and migration of SMCs into the intima to form a neointima. Platelet-derived growth factor (PDGF) is believed to play a role in this response to injury, but it has proven difficult to distinguish whether it is stimulating cell migration or cell proliferation, and whether the action is direct or indirect. To determine this, we created chimeric mice composed of both wild-type (WT) and marked PDGF receptor beta (PDGFRbeta)-deficient cells, and determined the consequences of PDGFRbeta expression for SMC participation in response to ligation of the left common carotid artery.