Targeting the vasculature in cardiometabolic disease

Abstract

Obesity has reached epidemic proportions and is a major contributor to insulin resistance (IR) and type 2 diabetes (T2D). Importantly, IR and T2D substantially increase the risk of cardiovascular (CV) disease. Although there are successful approaches to maintain glycemic control, there continue to be increased CV morbidity and mortality associated with metabolic disease. Therefore, there is an urgent need to understand the cellular and molecular processes that underlie cardiometabolic changes that occur during obesity so that optimal medical therapies can be designed to attenuate or prevent the sequelae of this disease. The vascular endothelium is in constant contact with the circulating milieu; thus, it is not surprising that obesity-driven elevations in lipids, glucose, and proinflammatory mediators induce endothelial dysfunction, vascular inflammation, and vascular remodeling in all segments of the vasculature. As cardiometabolic disease progresses, so do pathological changes in the entire vascular network, which can feed forward to exacerbate disease progression. Recent cellular and molecular data have implicated the vasculature as an initiating and instigating factor in the development of several cardiometabolic diseases. This Review discusses these findings in the context of atherosclerosis, IR and T2D, and heart failure with preserved ejection fraction. In addition, novel strategies to therapeutically target the vasculature to lessen cardiometabolic disease burden are introduced.

Figure 1. Schematic overview of systemic lipoprotein metabolism.

Triglyceride-rich lipoproteins such as VLDL and chylomicron (CM) are produced by the liver and gut, respectively, which distribute FFAs to various metabolic tissue(s) like muscle, heart, and adipose by interacting with the GPIHBP1-bound endothelial LPL enzyme. LPL activity is regulated by secreted ANGPTL3, ANGPTL4, and ANGPTL8. In subsequent peripheral lipolysis, VLDL and CM are converted into intermediate-density lipoprotein (IDL) and chylomicron remnants (CMRs). In the liver, HL liberates FFAs from IDL and converts them into LDL particles. HL activity is inhibited by ANGPTL4. The liver clears a large portion of remnants (LDL and CMRs) via hepatic receptors (LDLR and LRP1). Under hyperlipidemic conditions, some fractions of LDL or CMRs accumulate and oxidize in the subendothelial space of a large artery, which is subsequently taken up by macrophages that develop into foam cells within atherosclerotic plaques. Liver-derived Apo M complexed with sphingosine-1-phosphate (S1P) on HDL may modulate atherosclerotic plaque progression, first by interacting with endothelial S1P receptors (S1PRs) to maintain vascular integrity and suppress inflammation (lower left), and second, by reducing cholesterol overload of macrophages through the promotion of cholesterol efflux (center of figure).

Figure 2. Schematic overview of endothelial microvasculature in fatty acid uptake and systemic metabolism.

FFAs, either bound to albumin, or derived from LPL-mediated hydrolysis of circulating TRLs, traverse the endothelium by passive diffusion (flip-flop), receptor-mediated uptake (via CD36), and/or vectorial transport (via FATP4). FATP3 and ACSL1 and other acyl-CoA synthases likely facilitate vectorial transport, and mitochondrial ATP also appears to be important. ECs contain machinery to esterify FFAs into LDs, a DGAT1-dependent process that may protect ECs from ER stress. Conversely, LDs may be hydrolyzed, a largely ATGL-dependent process that liberates FFAs for mitochondrial oxidation and/or parenchymal delivery. Circulating bioactive molecules such as apelin can regulate FABP4 transcription, and bioactive molecules released from muscle cells, including 3-HIB and VEGFB, can regulate FATP3 and FATP4 expression. In addition, adipose tissue–derived ANGPT2 can activate endothelial α5β1 signaling to trigger FFA transport via CD36 and FATP3 into superficial adipose tissue. Adipose tissue–derived VEGFA signals via EC VEGFR2 to support both WAT and BAT angiogenesis and also plays a role in WAT “beiging” via EC VEGFR2 signaling and PDGF-CC release, which in turn activates preadipocytes to transform into BAT. In addition to FFA uptake, ECs participate in systemic metabolism. EC INSR signaling mediates insulin delivery to parenchymal cells via phosphorylation and activation of eNOS, leading to the production of NO, a potent vasodilator. INSR signaling also cooperates with CAV-1 to facilitate insulin TET via caveolae-dependent and -independent mechanisms. Insulin TET may also occur via a nonsaturable, INSR-independent fluid-phase process. In addition to insulin TET, NO increases blood flow and tissue perfusion to facilitate glucose and FFA delivery to parenchymal cells. Beyond blood flow, NO can partially activate AMPK via cGMP signaling, leading to GLUT-4 translocation to the plasma membranes of muscle cells. Moreover, via cysteine-S-nitrosylation reactions, NO modulates several key metabolic enzymes. Last, NO/cGMP signaling participates in the long-term regulation of mitochondrial metabolism via interactions with AMPK and PGC1α, a master transcriptional regulator of mitochondrial biogenesis and oxidative metabolism.