MicroRNA (miRNA/miRs) are small non-coding RNAs, approximately 18–25 nucleotides in length that are able to modulate post-transcriptional regulation of gene expression and function of protein-coding mRNAs in almost all key cellular processes, including, among others, angiogenesis, cell proliferation, migration, and apoptosis [
150]. miRNA is transcribed in the nucleus by RNA polymerase II as a primary transcript called pri-miRNA [
151]. It is recognized further by Drosha ribonuclease and its partner, the double-stranded RNA binding protein DGCR8 [
152] that go on to generate precursor miRNA (pre-miRNA) of approximately 70 nucleotides [
151]. The latter is then exported from the nucleus to the cytoplasm by exportin 5 (XPO5) [
153] and cleaved by RNase III enzyme Dicer, RNA-binding protein 2 (TARBP2), and AGO2 (DICER complex). The processing produces a double-stranded miRNA-miRNA duplex* [
154]. After separation of the two strands, the mature miRNA (the guide strand) is incorporated into the RNA-induced silencing complex (RISC), while the passenger miRNA strand denoted as * is incorporated into the RISC complex or degraded [
155]. The mature miRNA guides the AGO protein of the RISC to the complementary mRNA sequence on the target to repress its expression [
151]. The six to eight nucleotide sequence at the 5′ end of the loaded miRNA binds to the complementary sequence on the mRNA inducing their translational repression or degradation. Each miRNA is capable of regulating the expression of many genes; thus, each miRNA can simultaneously regulate a variety of cellular signaling pathways. Human platelets contain an abundant and diverse repertoire of miRNAs [
156,
157] that may regulate platelet mRNAs, protein synthesis, and reactivity [
157‐
159]. Platelets can release miRNAs directly into circulation as vesicle-free ribonucleoprotein complexes in association with Ago2 or high-density lipoproteins (HDL), or in exosomes, shedding vesicles, apoptotic bodies, and PMPs [
160‐
163]. Since platelets release PMPs upon activation, and PMPs are the most abundant microvesicles in the circulation, they carry a substantial amount of miRNAs that potentially control angiogenesis [
148,
157]. miRNA, e.g., miR-19, miR-21, miR-126, miR-133, miR-146, miR-223, has been detected in PMPs [
149]. Delivery of functional platelet miRNAs into ECs
via PMPs has also been demonstrated [
165,
166], where activated platelets released functional miRNAs that entered into ECs to regulate endothelial ICAM-1 expression [
165]. Furthermore, Laffont et al. [
166], in an elegant study, documented that platelets activated with thrombin release miR-223 preferentially through PMPs that can be internalized by ECs (human umbilical endothelial cells (HUVECs)), leading to the accumulation of platelet-derived miR-223. They also demonstrated that PMPs contain functional Ago2 × miR-223 complexes that are able to regulate (downregulate) expression of endogenous genes in recipient HUVECs, both at the mRNA (mRNA destabilization) and protein (inhibition of mRNA translation initiation) levels [
166]. Platelet-released miR-223 promotes advanced glycation end product-induced vascular EC apoptosis by targeting insulin-like growth factor 1 receptor [
167]. Platelet-derived miR-223 regulates P2Y
12 receptor expression in platelets, suggesting accelerated platelet activation and aggregation that may contribute to further stimulation of angiogenesis [
168]. Vascular endothelium damage increases the level of apoptotic bodies that induce the expression of SDH-1 in recipient ECs through importing miR-126 [
163]. Additionally, miR-126 targets the protein regulator of G-protein signaling 16 (RGS16) that is known to inhibit CXCR4 [
163]. Consequently, this enables CXCR4 to stimulate an autoregulatory feedback loop that increases the phosphorylation of ERK1/2 and enhances the production of SDF-1 [
163]. Furthermore, introduction of apoptotic bodies into an animal model by injection into the blood stream results in elevated levels of miR-126, and subsequent dysfunction of endothelium [
168]. It was demonstrated that miR-126 enhances vascular hemostasis by protecting endothelial integrity as it targets SPRED1 and PIK2R2 (inhibitors of EC growth signaling) [
169]. Platelet-derived miR-140 directly targets SDF-1 in fibroblasts, which may also contribute to angiogenesis [
170]. Furthermore, miR-221 and miR-222 target c-kit (tyrosine-protein kinase kit), endothelial nitric oxide synthase (eNOS), and p27/lip1 subsequently promote angiogenesis
in vivo in response to stem cell factor [
171,
172]. Given the immense diversity of platelet miRNA sequences [
157] and the number of cell types capable of exchanging information by intercellular transfer [
164], one quickly appreciates the complexity of intercellular communication. Though miRNAs may be critically involved in angiogenesis, their role in platelet secretion and platelet-mediated angiogenesis has not been fully elucidated. The net influence of miRNA and PMP-derived miRNA on angiogenesis warrants further study.