We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.

In the present study, we established an injury model of the mouse carotid artery. Complete removal of the endothelium was achieved with a flexible wire. A platelet monolayer covered the denuded surface, and damage to underlying medial smooth muscle cells (SMCs) was detected. Injection of [3H]thymidine was used to determine the replication index for medial SMCs, which was found to be 1.6% at 2 days after denudation and 9.8% at 5 days. SMCs were observed in the intima by day 8 (replication index, 66%), and by 2 weeks the intimal lesion had a similar cell content as the media. In most animals, repair of the endothelial lining was complete 3 weeks after injury. The present model will allow us to use transgenic animals to address questions relevant to vascular biology and atherosclerosis.

Intimal Platelets are thought to play a major role in the formation of arterial intimal lesions (1, 2) by releasing, at sites of endothelial denudation, growth factors that stimulate smooth muscle cell (SMC) growth. Support for the role of platelets in vivo comes from the key study of Friedman et al. (3), in which these authors showed that experimentally induced intimal lesion formation in rabbit arteries was significantly inhibited by prolonged thrombocytopenia. This study was interpreted by others to suggest that platelets play an important role in the induction of SMC replication, even though no cell cycle data were presented. An alternative hypothesis is that platelets and their mitogens were important in initiating migration of cells into the intima. In this regard, platelet-derived growth factor (PDGF) has been shown to be chemotactic for mesenchymal cells (4,5). The goal of this study was to determine whether, after balloon catheter denudation, inhibition of platelet adherence influenced SMCs in terms of early mRNA expression and cell proliferation. To accomplish this, we used a single injection of a polyclonal antibody against rat platelets that prevented their adherence to the subendothelium for more than 24 hr after injury. Using this protocol, we were able to show that the absence of platelets did not affect the early proliferation of SMCs in response to injury but did inhibit formation of intimal lesions. We conclude that after balloon catheter injury platelets play a minor role in promoting medial proliferation but are important in the stimulation of SMC migration into the intima.

Astrocytes are involved in non‐cell‐autonomous pathogenic cascades in amyotrophic lateral sclerosis (ALS); however, their role is still debated. We show that astrocytic NF‐κB activation drives microglial proliferation and leukocyte infiltration in the SOD1 (G93A) ALS model. This response prolongs the presymptomatic phase, delaying muscle denervation and decreasing disease burden, but turns detrimental in the symptomatic phase, accelerating disease progression. The transition corresponds to a shift in the microglial phenotype showing two effects that can be dissociated by temporally controlling NF‐κB activation. While NF‐κB activation in astrocytes induced a Wnt‐dependent microglial proliferation in the presymptomatic phase with neuroprotective effects on motoneurons, in later stage, astrocyte NF‐κB‐dependent microglial activation caused an accelerated disease progression. Notably, suppression of the early microglial response by CB2R agonists had acute detrimental effects. These data identify astrocytes as important regulators of microglia expansion and immune response. Therefore, stage‐dependent microglia modulation may be an effective therapeutic strategy in ALS.

Injury of an artery by passage of a balloon catheter causes both endothelial denudation and medial damage and produces a marked smooth muscle cell (SMC) proliferative response. In this study, the endothelium from rat carotid arteries was removed by use of a rotating loop of 5/0 monofilament suture (gentle denudation technique), which did not cause any detectable damage to the underlying medial cells but did cause platelet adherence. Expression of platelet-derived growth factor (PDGF) A-chain and PDGF receptor mRNA was comparable to that seen in ballooned carotids, but the medial SMC proliferative response to gentle denudation was markedly reduced when compared to that observed after balloon denudation (1.4% vs. 13.6%). Intimal lesions were only observed in those zones that remained denuded for more than 7 days. These results demonstrate that a denuding injury with no medial trauma is sufficient to induce intimal lesions and that the significantly higher proliferation seen in ballooned vessels might reflect a response of the medial cells to trauma that occurred during denudation. (Arteriosclerosis 10:1082-1087, November/December 1990) T he balloon catheter-injured artery has become the standard model for studying smooth muscle cell (SMC) proliferation in vivo, 123 and yet there is still little information as to what factors are involved in this process. One early hypothesis was that smooth muscle replication, which occurs soon after denudation, is initiated by platelet factors, but work by several groups has shown that platelet adherence to exposed subendothelium causes neither SMC replication nor intimal lesion formation.4 -9 Furthermore, in the total absence of platelets, balloon-injured arteries show a dramatic increase in SMC proliferation similar to that found in denuded arteries from control animals.10 These data strongly suggest that the SMC proliferation induced by mechanical injury is modulated by other, undetermined factors.A recent study by Majesky et al. 11 has shown that within hours after balloon injury, rat carotid arteries increase their expression of mRNA for platelet-derived growth factor (PDGF) A-chain and for the PDGF receptor. Therefore, injury to the arterial wall might induce an autocrine pathway in which SMC stimulate their own proliferation by synthesis of PDGF. Yet another explanation for the rapid increase in SMC proliferation might be