Angiogenesis, described as a biological process from which new blood vessels develop from pre-existent ones, is closely associated with cancers and ischemic cardiovascular diseases, also including but not limited to such physiological and pathological conditions as the menstrual cycle, wound healing, inflammation, Alzheimer’s disease, and diabetes. Importantly, changes in tissue vascularization via angiogenesis are critical in the pathophysiology of cancers and ischemic cardiovascular diseases and contribute to the disease progression. Therapeutic strategies stimulating functional angiogenesis under ischemic conditions or inhibiting abnormal angiogenesis in cancers have been tested and demonstrated significant therapeutic potential but these strategies have shown limited clinical efficacy, suggesting the need for a better understanding of the angiogenesis.

The typically accepted concept of angiogenesis or neovascularization broadly includes angiogenesis, arteriogenesis, and vasculogenesis [3], [4], [5], [6]. The nuance within each of these categories is important and the biology of neovascularization remains hotly debated. Among these three major processes of neovascularization, arteriogenesis has historically represented vascular remodeling and luminal diameter enlargement of existing vessels, or maturation of collateral vessels in response to increased blood flow [7]. Whether collateral development occurs de novo or through enlargement of existing vessels remains under active scientific debate [4], though patients with ischemic vascular diseases have been shown to spontaneously grow collateral vessels to effectively bypass arterial occlusions [7]. Arteriogenesis can also occur de novo by blood vessel expansion, and capillary arterialization that generates new arterioles from preexisting capillaries [8], [9]. De novo arteriogenesis (growth of new arterioles) also occurs within the tumor microenvironment (TME) [1], [10], [11], under ischemic conditions [2], [5] and in response to the stimulation of vascular endothelial growth factor (VEGF) in adult animals [11]. At the molecular level, delta-like ligand 4 (DLL4) and Notch signaling may connect sprouting angiogenesis to the development of new arteries [12].

To better explain and understand phenotypes of de novo arteriogenesis and reconcile the debate, we would like to propose and describe a concept of arteriolar angiogenesis to denote the development of new small arteries from the pre-existent vascular system under pathological conditions. We will emphasize endothelial cells (ECs), a fundamental and heterogenous cell type essential for angiogenesis and arteriogenesis. These ECs can also obtain organ-specific functional features through microenvironmental signals from non-vascular niche cells [13]. In doing so we will provide an overview of angiogenesis, define major regulators and current understanding specific to arteriolar angiogenesis, and discuss a new concept that dynamic angiogenic signaling regulates arteriolar angiogenesis rather than this process being simply regulated by changes in balance between angiogenic stimulators and angiogenesis inhibitors.

In addition, angiogenesis is known as a hallmark in tumor progression [14]. Pancreatic cancer is characterized by abnormal angiogenesis with high microvascular density accompied by low microvessel integrity, which may contribute to its early recurrence, metastasis and short survival after tumor resection [15]. However, anti-angiogenic therapeutic strategies demonstrate limited efficacy in preclinical models and clinical scenerios [5], [15], [16]. This may be due to an angiogenesis-mediated immunosuppressive microenvironment [17], in which the changes in the immune microenvironment mediated by vascular ECs in tumors may play an important role [18]. Several antiangiogenic drugs that were tested in human patients with pancreatic cancers demonstrated limited therapeutic efficacy [15]. Elpamotide, an epitope peptide derived from the amino acid sequence of VEGFR2, demonstrated an anti-angiogenic immunotherapeutic effect against cancer by inducing cytotoxic T lymphocytes to eliminate VEGFR2-positive human ECs in the clinical settings [15], [19], which is potentially useful in the treatment of pancreastic cancer with robust angiogenesis. It remains to be determined whether this therapeutic strategy can target mature tumor vessels that are formed through arteriolar angiogenesis and whether combination of anti-angiogenic strategies with immunotherapy increases therapeutic efficacy. Therefore, we will discuss the therapeutic potential of anti-angiogenic immunotherapeutic strategies in the context of pancreatic cancers. We anticipate that this review will provide a basic and mechanistic understanding of arteriolar angiogenesis with implications amenable to anti-angiogenic immunotherapy. The knowledge gained may yield valuable insights into therapeutic strategies that target neovascularization not only in pancreatic cancers but also in a variety of other disorders associated with abnormal and dysfunctional angiogenesis.