Molecular mechanisms of communication between innate immune cells and vascular cells in cancer and cardiovascular diseases

The immune-vascular crosstalk is a critical factor in cancer and cardiovascular diseases, driving disease progression through inflammatory, remodeling, and angiogenic pathways. Despite recent progress, the underlying molecular mechanisms that govern the interplay between vascular and immune cells remain elusive. Understanding these interactions provides opportunities for developing novel therapeutic strategies targeting immune and vascular components to improve treatment efficacy and patient outcomes. In this context, our work aimed to investigate the communication between innate immune cells (monocytes-macrophages) with endothelial cells and smooth muscle cells (SMC). Using different models of cellular cross-talk between monocyte/macrophages and vascular cells, our data reveal that: i) upon their interaction with monocytes, the molecular signatures of endothelial cells suffer transcriptomic changes in processes related to cytoskeleton regulation, focal adhesions, cellular junctions, and cell adhesion, as evaluated by RNAseq analysis, leading to changes in endothelial cells adherence to extracellular matrix, endothelial permeability, monocyte adhesion, and transmigration; ii) the SMC-monocyte interaction induced, in each cell type, an increased mRNA and protein expression of TNFα, IL-1β, IL-6, CX3CR1, MMP-2 and MMP-9, dependent by fractalkine - CX3CR1 axis dependent and by MAPK signaling and activation of NF-kB and AP-1 transcription factors; iii) when SMC communicated with macrophages (MAC), the SMC exhibits increased expression and activity of metalloproteases MMP-9, MMP-1, and augmented secretion of VEGF. Moreover, the conditioned media collected from MAC–SMC co-culture promoted endothelial cell tube formation in Matrigel, signifying an increased angiogenic effect. In addition, MAC exhibited a general increased expression of chemokines (with VCC-1 and GRO-α having the highest fold increase) and of interleukins such as IL-5 (∼8-fold) and IL-6 (∼4-fold) in MAC. When the cross talk was realized in the presence of resistin (adipose-derived cytokine), a predominant increase of interleukins (the highest fold increase: IL-6, IL-27, IL-23 and IL-5) and an augmented expression of chemokines such as MIP-1β, GRO-α and CCL1 was obtained. Cell communication in the presence of ficolin-2 (a pattern recognition molecule that activates the lectin complement pathway, contributing to innate immunity), induced pro-inflammatory phenotypes in both cell types gained with increased MCP-1, IL-6 and TLR4, in SMC (by activating ERK/MAPK and NF-KB signaling pathways) and IL-1β, IL-6, and MIP-1β in MAC, ensuing enhanced monocyte transmigration. All these data demonstrate that communication between immune cells and vascular cells affects factors and molecules that could alter processes such as inflammation, tissue remodeling, and angiogenesis, features that could directly dictate the regulation of both, cancer progression and cardiovascular diseases.