Coronary Microvascular Dysfunction: Epidemiology, Pathophysiology, Diagnosis, and Treatment

FIGURE 1. Overview of key pathological features of CMD and potential therapeutic mechanisms targeting the NRG‐1/ErbB pathway. CMD is primarily characterized by endothelial dysfunction, microvascular structural remodeling, and impaired vasodilation. At the molecular level, NRG‐1 activates ErbB receptors (ErbB1/3/4 and ErbB2) and the Notch signaling pathway, and may interact with the histone acetyltransferase GCN5, thereby upregulating anti‐inflammatory factors (such as IL‐10) and inhibiting pro‐inflammatory factors (such as IL‐1β). These effects suppress cell apoptosis, alleviate inflammatory responses, improve endothelial function, and promote cell survival and proliferation, ultimately alleviating CMD.

FIGURE 2. Core pathological mechanisms of CMD. (A) Structural changes: Compared with healthy microvessels, CMD microvessels exhibit medial thickening, vascular wall remodeling, luminal narrowing, and capillary rarefaction, leading to increased microcirculatory resistance. (B) Functional changes: Endothelial dysfunction results in reduced vasodilatory factors (e.g., NO) and increased vasoconstrictors (e.g., ET‐1, thromboxane), triggering vasoconstriction and spasm, along with inflammatory cell infiltration and microthrombus formation, further exacerbating microcirculatory perfusion impairment. (C) Molecular mechanisms: Oxidative stress (ROS) creates a vicious cycle through the Nox and p66Shc pathways, leading to eNOS uncoupling, reduced NO bioavailability, and activation of the RhoA/Rho kinase pathway, which promotes smooth muscle contraction, vascular spasm, and inflammatory responses, collectively driving the onset and progression of CMD.

FIGURE 3. Processing and maturation of NRG‐1 and its initiation of signal transduction through the ErbB receptor family. (A) Precursors of different NRG‐1 isoforms (Pro‐NRG‐1) are cleaved by BACE1 to generate mature NRG‐1, which harbors key functional modules including an Ig‐like domain, a spacer region, and an EGF‐like domain. (B) Upon binding to ErbB receptors, mature NRG‐1 induces the formation of homodimers or heterodimers. ErbB4 possesses a complete kinase domain and can form functional homodimers; ErbB3 lacks a kinase domain and cannot form homodimers; ErbB2 primarily serves as a co‐receptor involved in heterodimer assembly.

FIGURE 4. Schematic diagram of the mechanisms by which NRG‐1 activates the Raf‐MEK‐ERK, PI3K‐Akt‐mTOR, and Src/FAK signaling pathways through ErbB receptors. Upon binding to ErbB family receptors, NRG‐1 initiates three major downstream signaling pathways through homodimerization or heterodimerization. NRG‐1 binds to ErbB4 to form homodimers, or forms heterodimers with ErbB2 and ErbB3, thereby activating the Raf‐MEK‐ERK, PI3K‐Akt‐mTOR, and Src/FAK pathways, respectively. The Raf‐MEK‐ERK pathway is primarily involved in regulating cell metabolism, proliferation, and survival. The PI3K‐Akt‐mTOR pathway, mediated by ErbB2 heterodimerization or ErbB4 homodimerization, activates downstream HIF‐1α, promoting angiogenesis, cell metabolism, and survival. The Src/FAK pathway participates in cell survival and sarcomere maintenance through the formation of focal adhesion complexes. Together, these three pathways coordinate the biological functions of NRG‐1 in angiogenesis, cardiomyocyte protection, and cell growth regulation.

FIGURE 5. Schematic diagram of the mechanism by which NRG‐1 regulates endothelial cell function through the RhoA/ROCK signaling pathway. RhoA is converted into its active GTP‐bound form by guanine nucleotide exchange factors (GEFs), or inactivated into its GDP‐bound form by GTPase‐activating proteins (GAPs). Activated RhoA mediates multiple downstream effects through ROCK: it inhibits eNOS activity, reducing NO production and leading to impaired vasodilation; activates NADPH oxidase, promoting ROS production and exacerbating oxidative stress; and induces VE‐cadherin phosphorylation, disrupting adherens junction integrity and increasing endothelial barrier permeability. NRG‐1 can inhibit RhoA activation, thereby maintaining F‐actin cytoskeleton structure and preserving endothelial barrier function, suggesting its potential protective role in ameliorating vascular dysfunction.

FIGURE 6. Therapeutic effects of traditional Chinese medicine on CMD based on the NRG‐1/ErbB signaling pathway. Traditional Chinese medicine interventions include Qiliqiangxin capsule, Shenzhu Guanxin granule, Tongxinluo capsule, Liqi Huatan Huoxue (LQHTHX) formula, Astragalus, Xuefu Zhuyu decoction, Qishen Yiqi dripping pill, Naoxintong capsule, 20(S)‐protopanaxadiol, and Icariin. These interventions primarily exert their effects by activating the NRG‐1/ErbB signaling axis, thereby regulating multiple downstream signaling pathways such as PI3K/Akt, Raf/MEK/ERK, and JAK2/STAT3, which mediate a range of biological effects: improving vascular endothelial function (upregulating CD31, VEGF), inducing beneficial ventricular remodeling (inhibiting fibrosis and apoptosis), and promoting myocardial angiogenesis (increasing microvascular density, improving hemodynamics), thus exerting comprehensive therapeutic effects on CMD.