Aging of signal transduction pathways, and pathology.

The major cell signaling pathways, and their specific mechanisms of transduction, have been a subject of investigation for many years. As our understanding of these pathways advances, we find that they are evolutionarily well-conserved not only individually, but also at the level of their crosstalk and signal integration. Productive interactions within the key signal transduction networks determine success in embryonic organogenesis, and postnatal tissue repair throughout adulthood. However, aside from clues revealed through examining age-related degenerative diseases, much remains uncertain about imbalances within these pathways during normal aging. Further, little is known about the molecular mechanisms by which alterations in the major cell signal transduction networks cause age-related pathologies. The aim of this review is to describe the complex interplay between the Notch, TGFbeta, WNT, RTK-Ras and Hh signaling pathways, with a specific focus on the changes introduced within these networks by the aging process, and those typical of age-associated human pathologies.

A mathematical model of plasma membrane electrophysiology and calcium dynamics in vascular endothelial cells.

Vascular endothelial cells (ECs) modulate smooth muscle cell (SMC) contractility, assisting in vascular tone regulation. Cytosolic Ca(2+) concentration ([Ca(2+)](i)) and membrane potential (V(m)) play important roles in this process by controlling EC-dependent vasoactive signals and intercellular communication. The present mathematical model integrates plasmalemma electrophysiology and Ca(2+) dynamics to investigate EC responses to different stimuli and the controversial relationship between [Ca(2+)](i) and V(m). The model contains descriptions for the intracellular balance of major ionic species and the release of Ca(2+) from intracellular stores. It also expands previous formulations by including more detailed transmembrane current descriptions. The model reproduces V(m) responses to volume-regulated anion channel (VRAC) blockers and extracellular K(+) concentration ([K(+)](o)) challenges, predicting 1) that V(m) changes upon VRAC blockade are [K(+)](o) dependent and 2) a biphasic response of V(m) to increasing [K(+)](o). Simulations of agonist-induced Ca(2+) mobilization replicate experiments under control and V(m) hyperpolarization blockade conditions. They show that peak [Ca(2+)](i) is governed by store Ca(2+) release while Ca(2+) influx (and consequently V(m)) impacts more the resting and plateau [Ca(2+)](i). The V(m) sensitivity of rest and plateau [Ca(2+)](i) is dictated by a [Ca(2+)](i) "buffering" system capable of masking the V(m)-dependent transmembrane Ca(2+) influx. The model predicts plasma membrane Ca(2+)-ATPase and Ca(2+) permeability as main players in this process. The heterogeneous V(m) impact on [Ca(2+)](i) may elucidate conflicting reports on how V(m) influences EC Ca(2+). The present study forms the basis for the development of multicellular EC-SMC models that can assist in understanding vascular autoregulation in health and disease.