Emerging evidence supports a role for platelets in the progression of atherosclerosis in addition to an involvement in thrombotic vascular occlusion. Platelet Factor 4 (PF4), a chemokine released by activated platelets, stimulates several pro-atherogenic processes. Therefore, we examined the localization of PF4 and the homologous protein, Neutrophil Activating Protein-2 (NAP-2) in lesions representing the evolution of human atherosclerotic plaques. Carotid plaques from 132 patients with critical carotid stenosis and 6 autopsy specimens were studied. Clinical, histologic and immunohistochemical data were analyzed using a chi(2)-test. PF4 was detected in the cytoplasm of luminal and neovascular endothelium, in macrophages and in regions of plaque calcification. The presence of PF4 in macrophages and neovascular endothelium correlated with lesion grade (p = 0.004; p = 0.044). Staining of macrophages for PF4 correlated with the presence of symptomatic atherosclerotic disease (p = 0.028). In early lesions, PF4 was commonly found in macrophages of early lesions (Grade I/II), whereas NAP-2 was rarely present. In conclusion, correlation between PF4 deposition, lesion severity and symptomatic atherosclerosis suggests that persistent platelet activation may contribute to the evolution of atherosclerotic vascular lesions. These studies support the rationale for the chronic use of anti-platelet therapy in patients at risk for developing symptomatic atherosclerosis.

Abstract-Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca 2ϩ release events (Ca 2ϩ -sparks), trigger the activation of large-conductance Ca 2ϩ -activated K ϩ (BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca 2ϩ ] i release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca 2ϩ -sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BK␣ subunit was unchanged. The Ca 2ϩ -sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BK␤1 subunit confers Ca 2ϩ -sensitivity to BK channel complexes and both transcript and protein levels for BK␤1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BK␤1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension. (Circ Res. 2007;100:703-711.)

Retinal arterioles generate Ca(2+) sparks with characteristics that vary during different phases of the spontaneous Ca(2+)-signaling cycle. Sparks summate to produce sustained Ca(2+) transients associated with contraction and thus may play an important excitatory role in initiating vessel constriction. This deserves further study, not least because Ca(2+) sparks appear to inhibit contraction in many other smooth muscle cells.

Curtis TM. Kv1.5 is a major component underlying the A-type potassium current in retinal arteriolar smooth muscle.

A-type current is the major voltage-dependent K(+) current in retinal MVSM and appears to play a physiological role in suppressing cell excitability and contractility.