Fibrin is formed at sites of tissue injury and provides the temporary matrix needed to support the initial endothelial cell responses needed for vessel repair. Basic fibroblast growth factor (bFGF) also acts at sites of injury and stimulates similar vascular cell responses. We have, therefore, investigated whether there are specific interactions between bFGF and fibrinogen and fibrin that could play a role in coordinating these actions. Binding studies were performed using bFGF immobi-

Vascular development and response to injury are regulated by several cytokines and growth factors including the members of the fibroblast growth factor and vascular endothelial cell growth factor (VEGF) families. Fibrinogen and fibrin are also important in these processes and affect many endothelial cell properties. Possible specific interactions between VEGF and fibrinogen that could play a role in coordinating vascular responses to injury are investigated. Binding studies using the 165 amino acid form of VEGF immobilized on Sepharose beads and soluble iodine 125 (125I)–labeled fibrinogen demonstrated saturable and specific binding. Scatchard analysis indicated 2 classes of binding sites with dissociation constants (Kds) of 5.9 and 462 nmol/L. The maximum molar binding ratio of VEGF:fibrinogen was 3.8:1. Further studies characterized binding to fibrin using 125I-labeled VEGF- and Sepharose-immobilized fibrin monomer. These also demonstrated specific and saturable binding with 2 classes of sites havingKds of 0.13 and 97 nmol/L and a molar binding ratio of 3.6:1. Binding to polymerized fibrin demonstrated one binding site with a Kd of 9.3 nmol/L. Binding of VEGF to fibrin(ogen) was independent of FGF-2, indicating that there are distinct binding sites for each angiogenic peptide. VEGF bound to soluble fibrinogen in medium and to surface immobilized fibrinogen or fibrin retained its capacity to support endothelial cell proliferation. VEGF binds specifically and saturably to fibrinogen and fibrin with high affinity, and this may affect the localization and activity of VEGF at sites of tissue injury.

These data indicate that endogenously synthesized fibrinogen promotes the growth of lung and prostate cancer cells through interaction with FGF-2.

Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction. Endothelial cells and mononuclear phagocytes have important roles in the intracellular killing of rickettsiae upon activation by the effector molecules of innate and adaptive immunity. In overwhelming infection, immuno-suppressive effects contribute to the severity of illness. Rickettsia-host cell interactions involve host cell receptors for rickettsial ligands that mediate cell adhesion and, in some instances, trigger induced phagocytosis. Rickettsiae interact with host cell actin to effect both cellular entry and intracellular actin-based mobility. The interaction of rickettsiae with the host cell also involves rickettsial evasion of host defense mechanisms and exploitation of the intracellular environment. Signal transduction events exemplify these effects. An intriguing frontier is the array of rickettsial noncoding RNA molecules and their potential effects on the pathogenesis and transmission of rickettsial diseases. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Objective-Studies have shown improved survival in cancer patients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in M r on selected endothelial cell properties. Methods and Results-Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in M r . Cell proliferation was assessed by [ 3 H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94Ϯ2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58Ϯ8%) or 3-kDa LMWH (60Ϯ9%, Pϭ0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three-and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58Ϯ15% and 67Ϯ9% (PϽ0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant. Conclusions-Heparin inhibition of endothelial cell proliferation and organization requires a chain length of Ͼ8 saccharide units, with maximal inhibition at M r of 6 kDa. This M r dependence differs from that required for anticoagulant activity. Key Words: low molecular weight heparins Ⅲ cancer Ⅲ angiogenesis Ⅲ endothelium Ⅲ thrombosis U nfractionated heparin is a heterogeneous mixture of polysaccharide molecules with a mean M r between 12 and 15 kDa containing glycosaminoglycan chains from 200 to 300 saccharide units. 1 Low molecular weight heparins (LMWHs) are fragments of unfractionated heparin produced by controlled enzymatic or chemical depolymerization with lower mean M r between 3 and 6 kDa and chain lengths of 12 to 18 saccharide units. 2 These structural differences result in important functional and pharmacokinetic differences, inasmuch as LMWHs have an increased anti-Xa/anti-IIa activity ratio, reduced plasma protein binding, decreased interaction with platelets and platelet factor 4, a prolonged half-life, and increased bioavailability after subcutaneous administration. 2,3 These changes give LMWHs an improved therapeutic profile compared with unfractionated heparin and have led to their increasing use in the treatment of venous and arterial thrombosis. See page 1954Individual studies 4,5 and meta-analyses 6,7 have found significant improvements in 3-and 6-month mortality in patients with cancer who were treated with LMWHs compared with unfractionated heparin. This survival advantage was found in subgroups differing in age, sex, and primary site of malignancy and could not be attributed to differences in thrombosis or bleeding complications. 8 The mechanism of this effect remains unknown but appears to be independent of the anticoagulant action of LMWH and may be related to effects on the vasculature. Prior studie...