Connexin 37 Limits Thrombus Propensity by Downregulating Platelet Reactivity

Abstract

Background— Formation of platelet plug initiates hemostasis after vascular injury and triggers thrombosis in ischemic disease. However, the mechanisms leading to the formation of a stable thrombus are poorly understood. Connexins comprise a family of proteins that form gap junctions enabling intercellular coordination of tissue activity, a process termed gap junctional intercellular communication . Methods and Results— In the present study, we show that megakaryocytes and platelets express connexin 37 (Cx37). Deletion of the Cx37 gene in mice shortens bleeding time and increases thrombus propensity. Aggregation is increased in murine Cx37 −/− platelets or in murine Cx37 +/+ and human platelets treated with gap junction blockers. Intracellular microinjection of neurobiotin, a Cx37-permeant tracer, revealed gap junctional intercellular communication in platelet aggregates, which was impaired in Cx37 −/− platelets and in human platelets exposed to gap junction blockers. Finally, healthy subjects homozygous for Cx37–1019C, a prognostic marker for atherosclerosis, display increased platelet responses compared with subjects carrying the Cx37–1019T allele. Expression of these polymorphic channels in communication-deficient cells revealed a decreased permeability of Cx37–1019C channels for neurobiotin. Conclusions— We propose that the establishment of gap junctional communication between Cx37-expressing platelets provides a mechanism to limit thrombus propensity. To our knowledge, these data provide the first evidence incriminating gap junctions in the pathogenesis of thrombosis.

Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function

“…As a confirmation of this possibility, the mRNA of 16 Cxs were found more than 20 years later in megakaryocyctes, among which Cx37, Cx40 and Cx62 showed the highest expression patterns [134]. Some other studies reported the expression of several Cxs in platelets including Cx32, Cx37, Cx40 and Cx43 [134,135,136]. Formation of functional gap junction channels in platelet aggregates was demonstrated by several techniques allowing the tracking of fluorescent dyes (neurobiotin and calcein) that diffuse from one platelet to another [134,135].…”

“…Some other studies reported the expression of several Cxs in platelets including Cx32, Cx37, Cx40 and Cx43 [134,135,136]. Formation of functional gap junction channels in platelet aggregates was demonstrated by several techniques allowing the tracking of fluorescent dyes (neurobiotin and calcein) that diffuse from one platelet to another [134,135]. Interestingly, blocking or deleting Cx37 prevented the diffusion of this dye.…”

Multiple Roles of Connexins in Atherosclerosis- and Restenosis-Induced Vascular Remodelling

“…Upon activation, the morphology of the platelets changes and they express molecules to enhance their adhesion to ECs and inflammatory cells. Angelillo-Scherrer et al [111] recently demonstrated that platelets express Cx37 and that GJ communication between Cx37-expressing platelets provides a mechanism for limiting thrombus propensity. More recent studies seem to implicate the Cx37 and Cx40 hemichannels in thrombus formation as well, even though the authors leave unexplained how hemichannels may open in the presence of a fair amount of extra-cellular calcium needed to induce platelet aggregation [112,113].…”

Neutrophil Intercellular Communication in Acute Lung Injury: Emerging Roles of Microparticles and Gap Junctions

“…Neutrophils may additionally complex with platelets during sepsis (45). Because platelets are capable of forming functional connexons (46,47), these complexes may allow for neutrophil-platelet GJIC. Interestingly, the presence of circulating platelet-leukocyte conjugates was associated with improved outcomes in septic shock (30).…”