Progressive liver fibrosis, leading to cirrhosis, is the most common cause of liver failure and the hallmark of chronic liver disease. Liver fibrosis is a pathophysiological process triggered within the liver after injury to mediate tissue repair and wound-healing response. 1 Angiogenesis and vascular remodeling are strongly associated with progressive liver fibrosis. 2 Angiogenesis may have both beneficial effects, such as restoration of nutrient and oxygen delivery to underperfused tissue, and harmful effects, such as changes in signaling and alterations in vascular structural makeup. In any case, given that liver fibrosis and angiogenesis are coupled, it is rational to study the links between these two biological processes. Liver myofibroblasts (MFs) are the effector cells responsible for scar formation observed during fibrosis and cirrhosis. 3 In fact, the “myofibroblast hypothesis”(that MFs are the matrix-producing cells in liver injury) may rightly be deemed the “myofibroblast theory”(in the traditional language of science, in which a theory is a hypothesis verified so many times that is unlikely to be proven incorrect). It is increasingly recognized that MFs constitute a heterogeneous cell population that may derive from multiple cellular precursors. However, two cell populations predominate: MFs derived from hepatic stellate cells (HSCs) and those derived from portal fibroblasts (PFs). In the healthy liver, PFs are resident mesenchymal cells with a peribiliary distribution located in portal areas. 5, 6 Functions of quiescent PFs include regulation of extracellular matrix (ECM) turnover4, 5 and maintenance of cholangiocyte cell mass. 4, 5 In the fibrosing liver, PFs undergo myofibroblastic differentiation to give rise to PF-derived MFs, generally described as portal myofibroblasts (PMFs). It is worth noting that the terminology used for liver MF is often as confusing as it is descriptive, which has probably prevented its widespread adoption. Regardless, the phenotypic characterization of PMF has advanced a great deal in recent years, which has led to an increased understanding of PMF function. PMFs are typically characterized by expression of contractile alpha-smooth muscle actin filaments6, 7 and increased production of several ECM-associated proteins, such as collagen-1, 6-8 fibronectin, 8, 9 fibulin-2, 8, 9 and lysyl oxidase family members. 10 What had not been clear in studies of PMF was the presence of any link between PMF and angiogenesis. Thus, the goal of the study11 by Lemoinne et al. featured in the current issue of HEPATOLOGY was to evaluate the functional contribution of PMF to angiogenesis in vitro and in vivo. For that purpose, the strategy pursued by the investigators here was to initially establish a correlation between the spatial distribution of fibrogenic PMF and of newly formed hepatic blood vessels in fibrotic livers, then test PMF ability to promote angiogenesis in vitro and in vivo, and, finally, determine the identity of the proangiogenic mediator (s) involved and the underlying mechanisms. First, the investigators performed a transcriptome analysis on primary culture-activated rat PF and identified type 15 collagen alpha1 (Col15a1) as a novel cell marker for PMF. This interesting finding confirmed Col15a1 specificity in labeling PMF in healthy and injured livers of mice and humans in vitro and in vivo. It is important to note that expression of Col15a1 was not what would be expected if all PMFs were labeled; rather, a subset of PMF appeared to be Col15a1 positive. In fact, the distribution of Col15a1-expressing PMFs closely paralleled the appearance of the hepatic neovasculature human and experimental liver fibrosis. Overall, these results determined that PMF …