COVID-19 association with cardiovascular disease is thought to be due to endothelial cell inflammation. ACE2 interactions with SARS-CoV-2 spike protein S1 subunit are important to viral infection. In Dr. Montezano’s group, they questioned whether SARS-CoV-2 induces vascular inflammation via ACE2 and whether this is related to viral infection. By exposing human microvascular endothelial cells to recombinant S1p (rS1p), they observed that rS1p induces a potent inflammatory response via an ACE2-dependent manner, without affecting ACE2 activity. Their findings suggest that vascular inflammation in COVID-19 involves activation of ACE2-mediated pro-inflammatory signaling that may be unrelated to viral replication.