Defensin promotes the binding of lipoprotein(a) to vascular matrix.

Retention of lipoproteins within the vasculature is a central event in the pathogenesis of atherosclerosis. However, the signals that mediate this process are only partially understood. Prompted by putative links between inflammation and atherosclerosis, we previously reported that alpha-defensins released by neutrophils are present in human atherosclerotic lesions and promote the binding of lipoprotein(a) [Lp(a)] to vascular cells without a concomitant increase in degradation. We have now tested the hypothesis that this accumulation results from the propensity of defensin to form stable complexes with Lp(a) that divert the lipoprotein from its normal cellular degradative pathways to the extracellular matrix (ECM). In accord with this hypothesis, defensin stimulated the binding of Lp(a) to vascular matrices approximately 40-fold and binding of the reactants to the matrix was essentially irreversible. Defensin formed stable, multivalent complexes with Lp(a) and with its components, apoprotein (a) and low-density lipoprotein (LDL), as assessed by optical biosensor analysis, gel filtration, and immunoelectron microscopy. Binding of defensin/Lp(a) complexes to matrix was inhibited (>90%) by heparin and by antibodies to fibronectin (>70%), but not by antibodies to vitronectin or thrombospondin. Defensin increased the binding of Lp(a) (10 nmol/L) to purified fibronectin more than 30-fold. Whereas defensin and Lp(a) readily traversed the endothelial cell membranes individually, defensin/Lp(a) complexes lodged on the cell surface. These studies demonstrate that alpha-defensins released from activated or senescent neutrophils stimulate the binding of an atherogenic lipoprotein to the ECM of endothelial cells, a process that may contribute to lipoprotein accumulation in atherosclerotic lesions.

THE ONTOGENY OF POSTCRANIAL INTEGRATION IN THE COMMON TERN, STERNA HIRUNDO.

Empirical and theoretical work supports the concept that developmentally or functionally related characters tend to covary and hence evolve together. However, the dynamics of the developmental processes that establish within population covariance structures are not well understood. This paper focuses on a description of the relative growth of 16 postcranial skeletal elements during embryonic and posthatching development in the common tern, Sterna hirundo, and on a comparative analysis of ontogenetic and adult patterns of variation. Multivariate methods are used to assess the relative contributions of general growth and size-independent "shape" transformations during three major development phases. The observed patterns of integration generally correspond to functional units that tend to show greater relative growth during development immediately preceding when a unit will first be functionally required. Such age-dependent functional adaptations provide an opportunity for selection to act directly on ontogenies with consequences that will be age dependent. Size and shape contributions to adult covariances, which tend to be generated during different phases of development, appear to reflect ontogenetic integration patterns characteristic of periods when global constraints, such as overall size, are most relaxed, but more localized constraints, most likely linked to age-dependent functional requirements, are relatively intense.