<p>Cardiovascular diseases (CVD) are intricately linked to vascular dysfunction, with growing evidence implicating particulate matter (PM_2.5) as a major factor. This study addresses the urgent need to understand how PM_2.5 exposure influences cardiac vulnerability to ischemia-reperfusion (IR) injury by investigating the underlying mechanisms of vascular and myocardial alterations. The aim was to assess the progressive impact of PM_2.5 exposure on vascular and myocardial function, mainly focusing on mitochondrial integrity and calcification processes. Adult Wistar female rats were subjected to PM_2.5 at a concentration of 250 µg/m³ for 3 h daily over 1, 7, 14, and 21 days. Cardiac endurance to IR injury was assessed using the Langendorff perfusion method. Findings revealed that exposure for 7 days or more induced vascular calcification, upregulating calcification-related genes and causing calcium accumulation, while endothelial dysfunction and impaired vascular contractility manifested earlier. Myocardial calcification and hemodynamic impairments became evident after 14 days, correlating with progressive mitochondrial dysfunction in both vascular and cardiac tissues. By day 21, severe mitochondrial damage and elevated cardiac sensitivity to IR injury were observed, accompanied by increased metal deposition in the vasculature and myocardium. The study concludes that PM_2.5 exposure drives a cascade of vascular and myocardial alterations, with vascular dysfunction preceding myocardial calcification. These findings emphasize the need for strategies to mitigate PM_2.5 induced cardiovascular risks, particularly by targeting mitochondrial health and vascular integrity.</p>